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.

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.

Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature.

Major depressive disorders (MDDs) are often associated with a deficiency in long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs), as well as signs of low-grade inflammation. Epidemiological and dietary studies suggest that a high intake of fish, the major source of ω-3 PUFAs, is associated with lower rates of MDDs. Meta-analyses of randomized placebo-controlled ω-3 PUFAs intervention-trials suggest that primarily eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), is responsible for the proposed antidepressant effect. In this review, we dissect the current biological knowledge on EPA and DHA and their bioactive lipid metabolites to search for a pharmacological explanation of this, to date, unexplained clinical observation. Through enzymatic conversion by cyclooxygenase (COX), lipoxygenase (ALOX), and cytochrome P-450 monooxygenase (CYP), EPA and DHA are metabolized to major anti-inflammatory and pro-resolving lipid mediators. In addition, both ω-3 PUFAs are precursors for endocannabinoids, with known effects on immunomodulation, neuroinflammation, food intake and mood. Finally, both ω-3 PUFAs are crucial for the structure and organization of membranes and lipid rafts. While most biological effects are shared by these two ω-3 PUFAs, some distinct features could be identified: (1) The preferential CYP monooxygenase pathway for EPA and EPA derived eicosanoids; (2) The high CB2 receptor affinities of EPA-derived EPEA and its epoxy-metabolite 17,18-EEQ-EA, while the DHA-derived endocannabinoids lack such receptor affinities; (3) The competition of EPA but not DHA with arachidonic acid (AA) for particular glycerophospholipids. EPA and AA are preferentially incorporated into phosphatidylinositols, while DHA is mainly incorporated into phosphatidyl-ethanolamine, -serine and -choline. We propose that these distinct features may explain the superior antidepressant activity of EPA rich ω-3 PUFAs and that these are potential novel targets for future antidepressant drugs.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.

BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

Ventricular volumes across stages of schizophrenia and other psychoses.

OBJECTIVE: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis. METHODS: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years). RESULTS: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%). CONCLUSION: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes.

[Prevention and interventions for suicidal youth considerations for health professionionals in Switzerland]. / Suizidalität bei Adoleszenten - Prävention und Behandlung.

Adolescence is associated with a dramatic surge in suicide rate. While worldwide age-adjusted suicides rate per 100'000 in under 14-year olds are relatively low around 0.6, a dramatic increase to 7.4 can be observed in 15 ­ 19 year olds with suicide being one of the three leading causes of mortality in most countries in this age group. From 2000 to 2013 the Swiss annual average of completed suicides in 15 ­ 19 year olds was 33.1 (minimum 24; maximum 47). This corresponds to an average age-specific death rate of 7.6, which is slightly above the global mean. Suicide prevention and treatment of suicidality in adolescents is a complex underpinning. Subjectively experienced feelings of insufficiency, hopelessness and the feeling of worthlessness combined with concrete suicidal ideations and the capacity to act out are important indicators for assessing suicidal risk. Suicide attempts as the strongest risk factor for suicide should always be taken seriously, even if they occur in the context of situational crisis. Narcissistic personality traits or increased impulsivity are further indicators of risk. The early detection and effective treatment of mental disorders such as depression, anxiety disorders, bipolar-affective disorders or psychotic disorders provide a great opportunity to reduce the frequency of suicide attempts and suicide. Particular caution is required when co-morbid addictions are present. The maintenance or establishment of sustainable relationships with significant others is considered a key protecting factor. Increasing withdrawal from significant others is an important warning sign and needs urgent involvement of experts. In acute suicidality, the admission to a psychiatric hospital must be considered, if necessary against the will of affected adolescent and their relatives. Personality-related recurrent suicidal behavior requires specific treatment approaches taking into account the prevention of iatrogenic worsening of suicidal patterns.

An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

Self-Harm in Children and Adolescents Who Presented at Emergency Units During the COVID-19 Pandemic: An International Retrospective Cohort Study.

OBJECTIVE: To compare psychiatric emergencies and self-harm at emergency departments (EDs) 1 year into the pandemic, to early pandemic and pre-pandemic, and to examine the changes in the characteristics of self-harm presentations. METHOD: This retrospective cohort study expanded on the Pandemic-Related Emergency Psychiatric Presentations (PREP-kids) study. Routine record data in March to April of 2019, 2020, and 2021 from 62 EDs in 25 countries were included. ED presentations made by children and adolescents for any mental health reasons were analyzed. RESULTS: Altogether, 8,174 psychiatric presentations were recorded (63.5% female; mean [SD] age, 14.3 [2.6] years), 3,742 of which were self-harm presentations. Rate of psychiatric ED presentations in March to April 2021 was twice as high as in March to April 2020 (incidence rate ratio [IRR], 1.93; 95% CI, 1.60-2.33), and 50% higher than in March to April 2019 (IRR, 1.51; 95% CI, 1.25-1.81). Rate of self-harm presentations doubled between March to April 2020 and March to April 2021 (IRR, 1.98; 95% CI, 1.68-2.34), and was overall 1.7 times higher than in March to April 2019 (IRR, 1.70; 95% CI, 1.44-2.00). Comparing self-harm characteristics in March to April 2021 with March to April 2019, self-harm contributed to a higher proportion of all psychiatric presentations (odds ratio [OR], 1.30; 95% CI, 1.05-1.62), whereas female representation in self-harm presentations doubled (OR, 1.98; 95% CI, 1.45-2.72) and follow-up appointments were offered 4 times as often (OR, 4.46; 95% CI, 2.32-8.58). CONCLUSION: Increased pediatric ED visits for both self-harm and psychiatric reasons were observed, suggesting potential deterioration in child mental health. Self-harm in girls possibly increased and needs to be prioritized. Clinical services should continue using follow-up appointments to support discharge from EDs. DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial.

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.

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.

Relational memory in first episode psychosis: implications for progressive hippocampal dysfunction after illness onset.

OBJECTIVE: Verbal episodic memory deficits are prominent in schizophrenia and have also been found in first episode psychosis (FEP) and individuals at clinical risk of the disorder. The central role of the hippocampus in verbal memory processing and the consistent findings of hippocampal volume reductions in chronic patients have prompted the suggestion that impaired verbal memory performance may be a biomarker of schizophrenia. However, it is currently unclear as to when, during the early phase of psychosis, verbal memory performance becomes significantly impaired. The current study investigated verbal relational memory in FEP using a novel verbal paired associate task, and tested whether performance was dependent on phase of illness within FEP, where patients with a diagnosis of schizophrenia were considered to be in a more advanced stage than those with schizophreniform disorder. METHOD: Forty-seven currently psychotic FEP patients and 36 healthy non-psychiatric controls, aged 15-25 years old, completed a test comprising four trials of learning and cued recall of word pairs (denoted AB pairs), an interference phase comprising two trials with new second words (AC pairs), and finally cued recall for the original AB pairings. RESULTS: FEP patients performed similarly to controls on the relational memory task. There was no difference in performance between FEP patients who had a diagnosis of schizophrenia and those with a diagnosis of schizophreniform disorder. CONCLUSIONS: Verbal relational memory appears to be intact in FEP. This finding, along with chronic patient literature, suggests that decline in hippocampal and medial temporal lobe functioning occurs during later illness stages. Further research is needed to aid in the development of intervention strategies that may prevent decline in such cognitive domains at this crucial early stage of the illness.

Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: a longitudinal T2 relaxometry pilot study.

We used magnetic resonance imaging to examine the effect of ethyl-eicosapentaenoic acid (E-EPA) on hippocampal T(2) relaxation time in first episode psychosis patients at baseline and after 12 weeks of follow-up. There was an increase in T(2) in the placebo group but not in the E-EPA group, suggesting a neuroprotective effect of E-EPA treatment. In addition, the smaller the increase in T(2), the greater the improvement in negative symptoms.

The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis.

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.

Corrigendum: Relationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial.

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

Trajectories of symptom severity and functioning over a three-year period in a psychosis high-risk sample: A secondary analysis of the Neurapro trial.

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.

Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people.

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

Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis.

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

Medial temporal lobe glutathione concentration in first episode psychosis: a 1H-MRS investigation.

Glutathione (GSH) is implicated in the pathophysiology of schizophrenia. Previous brain spectroscopy studies, however, have been inconsistent, and there is little data available from first episode psychosis patients. This study compared brain GSH in a first episode cohort (n=30) to controls (n=18), using magnetic resonance spectroscopy (MRS), examining a temporal lobe voxel. Short-echo (TE 30 ms) acquisition proton MRS was performed on a 3T clinical magnetic resonance scanner. Comparison of the first-episode and control groups' GSH concentrations revealed a significant main effect of group (F(1,46)=4.7, p=0.035), but no main effect of hemisphere (F(1,46)=2.3, p=0.137) or group-by-side interactions (F(1,46)=0.4, p=0.513). Medial temporal lobe GSH concentrations in the first episode group were 22% higher than those in the control group. This study provides further evidence of significant perturbations in brain GSH in first episode psychosis, and supports a broader involvement of GSH in the pathophysiology of schizophrenia.

The International Study on General Practitioners and Early Psychosis (IGPS).

BACKGROUND: In much of the world, general practitioners (GPs) are the health professionals most frequently initially contacted when a young person is developing psychosis. However little is known about their expertise in assessing psychosis and its risk. METHODS: To assess the diagnostic patterns and treatment practices related to psychosis of GPs working in a range of health care systems, questionnaires were mailed to 12,516 randomly selected GPs in seven countries: Canada, Australia, New Zealand, England, Norway, Austria and the Czech Republic. Sites were defined as gatekeeping or non-gatekeeping, based on the primary care health system in effect at each site. A gatekeeping system (GK) is one which mandates that patients see a GP before in order to be referred to a specialist. By contrast, in a non-gatekeeping (nGK) system, individuals can seek help directly from specialists without authorization by a GP. RESULTS: Twenty-two percent (n=2784) GPs responded to the mailed questionnaire. They reported low prevalence of early psychosis seen in general practice. Using awareness of functional decline as a prognostic sign as a proxy, gatekeeping (GK) GPs were found to be superior in their knowledge of the signs and symptoms of early psychosis than were non-gatekeeping GPs. GP's with less knowledge as to early psychosis were more likely to refer individuals with suspected psychosis to specialists. GP's reported a preference for access to specialized outpatient services as compared with obtaining continuous medical education relevant to early psychosis. The duration of maintenance treatment recommended by GP's was less than that recommended in international guidelines. GP's also underestimated the risk for relapse after a first episode of psychosis. CONCLUSIONS: As GPs were largely unaware of features of early psychosis, such as functional decline, this should be the target of educational programs for GP's. However, the incidence of psychosis is low and GP's express a preference for access to appropriate referral over continuing medical education. Therefore, the development of specialized services for the assessment and care of patients who are in the early stages of developing schizophrenia may be warranted.

Relationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial.

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.