Has improved treatment contributed to the declining rate of transition to psychosis in ultra-high-risk cohorts?

BACKGROUND: The factors contributing to declining psychotic disorder transition rates in ultra-high-risk populations remain unclear. We examined the contribution of longitudinal changes in standard clinical treatment ('treatment as usual') to this decline. METHOD: An audit was conducted on 105 clinical files of patients who received standard care at a specialised ultra-high-risk service. The session notes of these files were quantified, allowing examination of treatment quantity, targets, psychotherapy, and medication. Differences in these aspects across patients' year of clinic entry were assessed. Variables with significant differences across years were examined using cox regression to assess their contribution to psychosis transition rates. RESULTS: Findings were that, as a function of patients' year of clinic entry, there were increases in: patients' number of sessions, cognitive behavioural therapy (CBT), problem and solving therapy. There was a relationship between baseline year cohort and psychosis transition rate, with lower rates observed in more recent cohorts. When changes in treatment between cohorts were adjusted for, the relationship between baseline year cohort and transition rate disappeared. The relationship between baseline year and transition rate was attenuated most by increases in CBT. CONCLUSION: Changes in standard treatment, particularly increases in CBT, may have contributed to the decline in psychosis risk observed in recent ultra-high-risk cohorts, although these variables do not fully explain this trend. Implications for clinical practice, prediction and intervention research are discussed. Future ultra-high-risk research should investigate the impact of other treatment factors, such as therapeutic alliance.

Toxoplasma gondii, Herpesviridae and long-term risk of transition to first-episode psychosis in an ultra high-risk sample.

BACKGROUND: Ultra high-risk (UHR) criteria were introduced to identify people at imminent risk of developing psychosis. To improve prognostic accuracy, additional clinical and biological risk factors have been researched. Associations between psychotic disorders and infections with Toxoplasma gondii and Herpesviridae have been found. It is unknown if exposure to those pathogens increases the risk of transition to psychosis in UHR cohorts. METHODS: We conducted a long-term follow-up of 96 people meeting UHR criteria, previously seen at the Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service in Melbourne, Australia. Transition to psychosis was assessed using the Comprehensive Assessment of the At-Risk Mental State (CAARMS) and state public mental health records. The relationship between IgG antibodies to Herpesviridae (HSV-1, HSV-2, CMV, EBV, VZV) and Toxoplasma gondii and risk for transition was examined with Cox regression models. RESULTS: Mean follow-up duration was 6.46 (±3.65) years. Participants who transitioned to psychosis (n = 14) had significantly higher antibody titers for Toxoplasma gondii compared to those who did not develop psychosis (p = 0.03). After adjusting for age, gender and year of baseline assessment, seropositivity for Toxoplasma gondii was associated with a 3.6-fold increase in transition hazard in multivariate Cox regression models (HR = 3.6; p = 0.036). No significant association was found between serostatus for Herpesviridae and risk of transition. CONCLUSIONS: Exposure to Toxoplasma gondii may contribute to the manifestation of positive psychotic symptoms and increase the risk of transitioning to psychosis in UHR individuals.

The prognostic significance of attenuated psychotic symptoms in help-seeking youth.

BACKGROUND: Recent findings suggest that attenuated psychotic symptoms (APS) might serve as a risk factor for general mental health impairment in help-seeking youth. The current study was designed to test this possibility by examining the prognostic significance of APS in a large cohort of help-seeking youth not selected for psychosis risk. METHOD: 465 youth aged 12-25 referred to general youth mental health services were grouped as either APS + or APS- based on whether or not they met 'ultra high risk' for psychosis APS risk criteria as assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS). They completed clinical assessments at baseline and at 12-month follow-up, measuring a range of psychopathology (depression, anxiety, eating disorders, general psychological distress, substance abuse) and psychosocial functioning. RESULTS: APS + had significantly poorer outcomes at 12-months on a range of clinical variables, even after adjusting for baseline scores and amount of treatment received. However, the APS + group showed greater improvement in functioning at follow-up compared to APS-. CONCLUSION: Attenuated psychotic symptoms are a prognostic indicator of persistent transdiagnostic mental health problems and reduced response to treatment in help-seeking youth over the short term. Hence, it is critical to screen and assess attenuated psychotic symptoms at the primary and secondary mental health services level, especially given that these subclinical symptoms are rarely voluntarily reported.

Basic symptoms in young people at ultra-high risk of psychosis: Association with clinical characteristics and outcomes.

There has been limited research into the predictive value of basic symptoms and their relationship with other psychopathology in patients identified using the 'ultra high risk' (UHR) for psychosis approach. The current study investigated whether basic symptoms, specifically cognitive disturbances (COGDIS), were associated with a greater risk of transition to psychotic disorder and persistent attenuated psychotic symptoms (APS) at medium term follow-up (mean = 3.4 years) in UHR patients, as well as with general psychopathology at baseline. The sample included 304 UHR participants (mean age = 19.12 years) involved in an international multicenter trial of omega-3 fatty acids. UHR individuals who also met the COGDIS criteria (basic symptoms risk criteria) did not have a greater risk of transition than those who met the UHR criteria alone. However, meeting COGDIS risk criteria was associated with a greater likelihood of meeting the UHR attenuated psychotic symptoms risk group (i.e., having persistent attenuated psychotic symptoms) at 12-month follow-up (odds ratio = 1.85; 95% CI = 1.03, 3.32). Greater severity of cognitive basic symptoms was also independently associated with more severe general psychopathology at study entry. The findings do not support the notion that combined risk identification approaches (UHR and basic symptoms) aid in the identification of individuals at greatest risk of psychosis, although this interpretation is limited by the modest transition to psychosis rate (13%) and the time of follow up. However, the findings indicate that basic symptoms may be a clinically useful marker of more severe general psychopathology in UHR groups and risk for persistent attenuated psychotic symptoms.

ENACT: a protocol for a randomised placebo-controlled trial investigating the efficacy and mechanisms of action of adjunctive N-acetylcysteine for first-episode psychosis.

BACKGROUND: First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N-acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups. METHODS/DESIGN: ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15-25 years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration. DISCUSSION: Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ID: ACTRN12618000413224. Registered on 21 March 2018.

Dynamic prediction of transition to psychosis using joint modelling.

Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n = 304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.

NEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders-medium-term follow-up and clinical course.

This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6-12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11-13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.

Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naïve first-episode psychosis patients.

BACKGROUND: Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naïve individuals with first acute episode of psychosis (FEP). METHOD: The study involved 27 drug-naïve FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T1-weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). RESULTS: (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). CONCLUSION: Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms.

Duration of untreated psychosis and neurocognitive functioning in first-episode psychosis: a systematic review and meta-analysis.

BACKGROUND: Previous reviews suggest there is minimal evidence for an association between duration of untreated psychosis (DUP) and neurocognition. This is based on tallied findings of studies with small samples and neurocognition viewed as a single construct. We aimed to conduct a systematic review and meta-analysis examining the association between DUP and individual neurocognitive domains and tests in first-episode psychosis (FEP). METHOD: MOOSE and PRISMA guidelines were followed. Forty-three studies involving 4647 FEP patients were included. For studies providing correlations between DUP and neurocognition, 12 separate meta-analyses were performed based on neurocognitive domains/indices. The influence of demographic/clinical variables was tested using weighted linear meta-regression analyses. RESULTS: The relationship between DUP and most neurocognitive domains/indices was not significant. Longer DUP was associated with a larger cognitive deterioration index, i.e. current minus premorbid intellectual functioning (N = 4; mean ES -0.213, 95% confidence interval (CI) (-0.344 to -0.074), p = 0.003). Findings were homogeneous, with no evidence of publication bias or significant influence from moderators. For studies providing mean and standard deviations for neurocognitive measures and DUP, 20 meta-regressions were performed on individual neurocognitive tests. One significant finding emerged showing that longer DUP was associated with fewer Wisconsin Card Sorting Test-perseverative errors (mean ES -0.031, 95% CI (-0.048 to -0.013), p < 0.001). Exploratory meta-regressions in studies with mean DUP <360 days showed longer DUP was significantly associated with poorer performance on Trail Making Test A and B and higher Full-Scale IQ. CONCLUSION: There may not be a generalised association between DUP and neurocognition, however, specific cognitive functions may be associated with longer DUP or delayed help-seeking.

The Ultra-High-Risk for psychosis groups: Evidence to maintain the status quo.

Individuals are considered Ultra-High-Risk (UHR) for psychosis if they meet a set of standardised criteria including presumed genetic vulnerability (Trait), or a recent history of Attenuated Psychotic Symptoms (APS) or Brief Limited Intermittent Psychotic Symptoms (BLIPS). Recent calls to revise these criteria have arisen from evidence that Trait, APS and BLIPS groups may transition to psychosis at different rates. Concurrently, it has become clear that the UHR status confers clinical risk beyond transition to psychosis. Specifically, most UHR individuals will not develop psychosis, but will experience high rates of non-psychotic disorders, persistent APS and poor long-term functional outcomes. Rather than focus on transition, the present study investigated whether UHR groups differ in their broader clinical risk profile by examining baseline clinical characteristics and long-term outcomes other than transition to psychosis. Four UHR groups were defined: Trait-only, APS-only, Trait+APS, and any BLIPS. Participants (N=702) were recruited upon entry to early intervention services and followed-up over a period of up to 13years (mean=4.53, SD=3.84). The groups evidenced similar symptom severity (SANS for negative symptoms, BPRS for positive and depression/anxiety symptoms) and psychosocial functioning (SOFAS, GAF, QLS) at baseline and follow-up as well as similar prevalence of non-psychotic disorders at follow-up. Our findings demonstrate that UHR groups evidence a similar clinical risk profile when we expand this beyond transition to psychosis, and consequently support maintaining the existing UHR criteria.

Omega-6 to omega-3 polyunsaturated fatty acid ratio and subsequent mood disorders in young people with at-risk mental states: a 7-year longitudinal study.

While cross-sectional studies suggest that patients with mood disorders have a higher ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) and lower levels of omega-3 PUFAs, it is unknown if a high n-6/3 ratio indicates vulnerability for depression. We tested this hypothesis in a 7-year follow-up study of young individuals with an ultra-high risk (UHR) phenotype. We conducted a secondary analysis of the Vienna omega-3 study, a longitudinal study of omega-3 PUFAs in individuals at UHR for psychosis (n=69). Levels of n-6 and n-3 PUFAs were measured in the phosphatidylethanolamine fraction of erythrocyte membranes at intake into the study. Mood disorder diagnosis was ascertained with the Structured Clinical Interview for DSM-IV-TR and confirmed by review of medical records and interviews of caregivers. A higher n-6/3 PUFA ratio at baseline predicted mood disorders in UHR individuals over a 7-year (median) follow-up (odds ratio=1.89, 95% CI=1.075-3.338, P=0.03). This association remained significant after adjustment for age, gender, smoking, severity of depressive symptoms at baseline and n-3 supplementation. Consistent results were obtained for individual PUFAs, including lower levels of eicosapentaenoic acid and docosahexaenoic acid. The predictive capacity of these findings was specific to mood disorders as no associations were found for any other psychiatric disorder. To our knowledge, our data provide the first prospective evidence that the n-6/3 PUFA ratio is associated with an increased risk for mood disorders in young people exhibiting an UHR phenotype. These findings may have important implications for treatment and risk stratification beyond clinical characteristics.

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia.

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

White matter connectivity disruptions in early and chronic schizophrenia.

BACKGROUND: White matter disruptions in schizophrenia have been widely reported, but it remains unclear whether these abnormalities differ between illness stages. We mapped the connectome in patients with recently diagnosed and chronic schizophrenia and investigated the extent and overlap of white matter connectivity disruptions between these illness stages. METHODS: Diffusion-weighted magnetic resonance images were acquired in recent-onset (n = 19) and chronic patients (n = 45) with schizophrenia, as well as age-matched controls (n = 87). Whole-brain fiber tracking was performed to quantify the strength of white matter connections. Connections were tested for significant streamline count reductions in recent-onset and chronic groups, relative to separate age-matched controls. Permutation tests were used to assess whether disrupted connections significantly overlapped between chronic and recent-onset patients. Linear regression was performed to test whether connectivity was strongest in controls, weakest in chronic patients, and midway between these extremities in recent-onset patients (controls > recent-onset > chronic). RESULTS: Compared with controls, chronic patients displayed a widespread network of connectivity disruptions (p < 0.01). In contrast, connectivity reductions were circumscribed to the anterior fibers of the corpus callosum in recent-onset patients (p < 0.01). A significant proportion of disrupted connections in recent-onset patients (86%) coincided with disrupted connections in chronic patients (p < 0.01). Linear regression revealed that chronic patients displayed reduced connectivity relative to controls, while recent-onset patients showed an intermediate reduction compared with chronic patients (p < 0.01). CONCLUSIONS: Connectome pathology in recent-onset patients with schizophrenia is confined to select tracts within a more extensive network of white matter connectivity disruptions found in chronic illness. These findings may suggest a trajectory of progressive deterioration of connectivity in schizophrenia.

Erythrocyte glutathione levels as long-term predictor of transition to psychosis.

A high proportion of individuals deemed at elevated risk for psychosis will actually never progress to develop the illness. Pharmaceutical intervention may not be necessary in these cases, and may in fact be damaging depending on the invasiveness of the treatment strategy. This highlights the need for biomarkers that are better able to reliably differentiate between at-risk individuals who will subsequently transition to psychosis and those who will not. Low glutathione (GSH) levels have been observed in schizophrenia and in patients with first-episode psychosis. The aim of this study was to determine the predictive value of erythrocyte GSH levels on the transition to psychosis in individuals at risk of developing the illness. Erythrocyte GSH levels were measured in 36 at-risk individuals, 15 of whom had transitioned to psychosis at the 7-year follow-up. Univariate Cox regression analysis showed that transition to psychosis at the 7-year time point was significantly associated with low GSH levels at baseline. The area under the receiving operating characteristic curve was 0.819, indicating that GSH can be considered a good predictor of outcome. Although these results need to be replicated, adding the criterion 'low erythrocyte GSH' to the set of criteria used to identify individuals at risk of psychosis may be indicated.

Substance use in youth at risk for psychosis.

BACKGROUND: People with schizophrenia have high rates of substance use which contributes to co-morbidity and premature mortality. Some evidence suggests people at-risk for psychosis have high rates of substance use. We aimed to assess substance use in a help-seeking cohort, comparing those at-risk and not at-risk for psychosis, and to establish any relationship with clinical symptoms. METHOD: Participants were help-seeking youth presenting to mental health services in Sydney and Melbourne. 279 (34.8%) were at-risk for psychosis, and 452 (56.4%) did not meet criteria for a psychotic disorder or risk for psychosis. The excluded individuals were made up of 59 (7.4%) young people who met criteria for a psychotic disorder and 11 (1.4%) who were unable to be evaluated. We assessed the association of substance use involvement with risk status and clinical symptoms using multivariate regression. RESULTS: Individuals at-risk for psychosis had significantly higher tobacco, alcohol and cannabis use than those not at-risk. Multivariate analysis revealed at-risk status was significantly associated with higher alcohol involvement scores when adjusting for age and gender, but no association was found for cannabis or tobacco. At-risk status was no longer associated with alcohol involvement when cannabis or tobacco use was added into the analysis. CONCLUSION: Tobacco smoking, alcohol consumption and cannabis use are common in help-seeking youth, particularly those at-risk for psychosis. It is important to consider co-occurring use of different substances in adolescents. Early substance misuse in this phase of illness could be targeted to improve physical and mental health in young people.

Prediction of transition from ultra-high risk to first-episode psychosis using a probabilistic model combining history, clinical assessment and fatty-acid biomarkers.

Current criteria identifying patients with ultra-high risk of psychosis (UHR) have low specificity, and less than one-third of UHR cases experience transition to psychosis within 3 years of initial assessment. We explored whether a Bayesian probabilistic multimodal model, combining baseline historical and clinical risk factors with biomarkers (oxidative stress, cell membrane fatty acids, resting quantitative electroencephalography (qEEG)), could improve this specificity. We analyzed data of a UHR cohort (n=40) with a 1-year transition rate of 28%. Positive and negative likelihood ratios were calculated for predictor variables with statistically significant receiver operating characteristic curves (ROCs), which excluded oxidative stress markers and qEEG parameters as significant predictors of transition. We clustered significant variables into historical (history of drug use), clinical (Positive and Negative Symptoms Scale positive, negative and general scores and Global Assessment of Function) and biomarker (total omega-3, nervonic acid) groups, and calculated the post-test probability of transition for each group and for group combinations using the odds ratio form of Bayes' rule. Combination of the three variable groups vastly improved the specificity of prediction (area under ROC=0.919, sensitivity=72.73%, specificity=96.43%). In this sample, our model identified over 70% of UHR patients who transitioned within 1 year, compared with 28% identified by standard UHR criteria. The model classified 77% of cases as very high or low risk (P>0.9, <0.1) based on history and clinical assessment, suggesting that a staged approach could be most efficient, reserving fatty-acid markers for 23% of cases remaining at intermediate probability following bedside interview.

Self reported rates of criminal offending and victimization in young people at-risk for psychosis.

A significant relationship exists between experiencing psychosis and both engaging in criminal offending and being a victim of crime. A substantial proportion of violence and offending occurs during the first episode of psychosis, but it is unclear whether such behaviour is also evident in the earlier pre-psychotic stage of illness. As part of a prospective study of young people who were seeking help for mental health problems, we enquired about participants' experiences of being charged and/or convicted of a criminal offence and being a victim of crime. This paper uses cross-sectional baseline data to compare the rates of these forensic outcomes in participants at-risk of psychosis (n=271) with those not at-risk (n=440). Univariate logistic regression showed that the at-risk for psychosis group was significantly more likely than the not at-risk participants to report having been charged by police (11.1% vs 5.9%; p=.015) and convicted by the courts (4.4% vs. 1.6%; p=0.028) with a non-violent offence, as well as to have been convicted of any criminal offence (6.3% vs. 3.0%; p=0.037). The at-risk were also more likely to report having been a victim of crime (23.7% vs 14.0%; p=.002), particularly violent victimization (16.5% vs 8.2%; p=.001). In multivariate logistic regression analyses, being at-risk for psychosis remained a significant predictor of three of the four outcome measures after controlling for other known covariates such as gender, age, substance misuse and unemployment. This is the first study to demonstrate that, relative to their non-psychotic help-seeking counterparts, young people at-risk for psychosis are at higher risk of forensic outcomes, particularly violent crime victimization.

Predictors of treatment response in young people at ultra-high risk for psychosis who received long-chain omega-3 fatty acids.

Previous efforts in the prospective evaluation of individuals who experience attenuated psychotic symptoms have attempted to isolate mechanisms underlying the onset of full-threshold psychotic illness. In contrast, there has been little research investigating specific predictors of positive outcomes. In this study, we sought to determine biological and clinical factors associated with treatment response, here indexed by functional improvement in a pre-post examination of a 12-week randomized controlled intervention in individuals at ultra-high risk (UHR) for psychosis. Participants received either long-chain omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) or placebo. To allow the determination of factors specifically relevant to each intervention, and to be able to contrast them, both treatment groups were investigated in parallel. Univariate linear regression analysis indicated that higher levels of erythrocyte membrane α-linolenic acid (ALA; the parent fatty acid of the ω-3 family) and more severe negative symptoms at baseline predicted subsequent functional improvement in the treatment group, whereas less severe positive symptoms and lower functioning at baseline were predictive in the placebo group. A multivariate machine learning analysis, known as Gaussian Process Classification (GPC), confirmed that baseline fatty acids predicted response to treatment in the ω-3 PUFA group with high levels of sensitivity, specificity and accuracy. In addition, GPC revealed that baseline fatty acids were predictive in the placebo group. In conclusion, our investigation indicates that UHR patients with higher levels of ALA may specifically benefit from ω-3 PUFA supplementation. In addition, multivariate machine learning analysis suggests that fatty acids could potentially be used to inform prognostic evaluations and treatment decisions at the level of the individual. Notably, multiple statistical analyses were conducted in a relatively small sample, limiting the conclusions that can be drawn from what we believe to be a first-of-its-kind study. Additional studies with larger samples are therefore needed to evaluate the generalizability of these findings.

Transitions Study of predictors of illness progression in young people with mental ill health: study methodology.

AIM: An estimated 75% of mental disorders begin before the age of 24 and approximately 25% of 13-24-year-olds are affected by mental disorders at any one time. To better understand and ideally prevent the onset of post-pubertal mental disorders, a clinical staging model has been proposed that provides a longitudinal perspective of illness development. This heuristic model takes account of the differential effects of both genetic and environmental risk factors, as well as markers relevant to the stage of illness, course or prognosis. The aim of the Transitions Study is to test empirically the assumptions that underpin the clinical staging model. Additionally, it will permit investigation of a range of psychological, social and genetic markers in terms of their capacity to define current clinical stage or predict transition from less severe or enduring to more severe and persistent stages of mental disorder. METHOD: This paper describes the study methodology, which involves a longitudinal cohort design implemented within four headspace youth mental health services in Australia. Participants are young people aged 12-25 years who have sought help at headspace and consented to complete a comprehensive assessment of clinical state and psychosocial risk factors. A total of 802 young people (66% female) completed baseline assessments. Annual follow-up assessments have commenced. CONCLUSIONS: The results of this study may have implications for the way mental disorders are diagnosed and treated, and progress our understanding of the pathophysiologies of complex mental disorders by identifying genetic or psychosocial markers of illness stage or progression.