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Advances in psychopharmacology have been significantly slower to evolve than in other disciplines of medicine and therefore investigation into novel therapeutic approaches is required. Additionally, concurrent metabolic conditions are prevalent among people with mental disorders. Metformin is a widely used hypoglycaemic agent that is now being studied for use beyond diabetes management. Evidence is emerging that metformin has multiple effects on diverse neurobiological pathways and consequently may be repurposed for treating mental illness. Metformin may have beneficial neuroimmunological, neuroplastic, neuro-oxidative and neuro-nitrosative effects across a range of psychiatric and neurodegenerative illnesses. Mechanisms include glucose lowering effects and effects on AMP-activated protein kinase (AMPK) signalling, however the best evidence for clinical benefit is through the glucose lowering effects, with other mechanisms less supported by the current evidence base. This narrative review aims to draw together the existing evidence for use of metformin as a psychopharmaceutical and present the role of metformin in the context of physical and psychiatric ill health, including metabolic, endocrinological and cancer domains. It not only has therapeutic potential in medical comorbidity but may have potential in core illness domains.

BACKGROUNDPreventing or delaying the onset of psychosis requires identification of those at risk for developing psychosis. For predictive purposes, the prodrome – a constellation of symptoms which may occur before the onset of psychosis – has been increasingly recognized as having utility. However, it is unclear what proportion of patients are expected to experience a prodrome or how this varies according to the definition used.METHODSWe conducted a systematic review and meta-analysis of studies of patients with psychosis with the objective of determining the proportion of patients who experienced a prodrome prior to psychosis onset. Inclusion criteria included a consistent prodrome definition and reporting the proportion of patients who experienced a prodrome. We excluded studies of only patients with a prodrome or solely substance-induced psychosis, qualitative studies without prevalence data, conference abstracts, and case reports/case series. We searched Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Web of Science Core Collection (Clarivate), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, APA PsycBooks (Ovid), ProQuest Dissertation & Thesis, on March 3, 2021. Studies were assessed for quality using the Critical Appraisal Checklist for Prevalence Studies. Narrative synthesis and proportion meta-analysis were used to estimate prodrome prevalence. I2and predictive interval were used to assess heterogeneity. Subgroup analyses were used to probe sources of heterogeneity. (PROSPERO ID: CRD42021239797).RESULTSSeventy-one articles were included, representing 13,774 patients. Studies varied significantly in terms of methodology and prodrome definition used. The random effects proportion meta-analysis estimate for prodrome prevalence was 78.3% (95% CI= 72.8-83.2); heterogeneity was high (I297.98% [95% CI= 97.71-98.22]); and the prediction interval was wide (95% PI= 0.411-0.936). There were no meaningful differences in prevalence between grouped prodrome definitions, and subgroup analyses failed to reveal a consistent source of heterogeneity.CONCLUSIONSThis is the first meta-analysis on the prevalence of a prodrome prior to the onset of first episode psychosis. The majority of patients (78.3%) were found to experience a prodrome prior to psychosis onset. However, findings are highly heterogenous across study and no definitive source of heterogeneity was found. As most studies were retrospective in nature, recall bias likely affects these results. While the large majority of patients with psychosis experience a prodrome in some form, it is unclear if the remainder of patients experience no prodrome, or if ascertainment methods employed in the studies were not sensitive to their experiences. Given widespread investment in indicated prevention of psychosis through prospective identification and intervention during the prodrome, a resolution of this question as well as a consensus definition of the prodrome is much needed in order to effectively direct services, and may be accomplished through novel, densely sampled prospective cohort studies.

Services for young people identified as having an 'at-risk mental state' (ARMS) aim to prevent transition to first-episode psychosis (FEP), in addition, early intervention services for other mental health disorders have also been developed. The aim of the current study was to determine the proportion of young people attending a specialist FEP service who had been referred via other early intervention clinics, including an ARMS clinic, and compare the characteristics to those who presented directly to the FEP service.We included young people diagnosed with FEP who received treatment at Orygen between 01.01.2012 and 31.12.2016. We examined rates of direct entry to the First Episode Psychosis service and rates from other early intervention services, specifically ARMS, personality disorders, mood disorders and a primary care youth mental health service clinics.1138 young people were diagnosed with a FEP, of whom 13.7% first attended an ARMS clinic and a further 7.6% attended other youth mental health services. Individuals who first presented to an ARMS clinic were more likely to be female, younger, and less likely to be migrants or use substances. Rates of both voluntary and involuntary hospital admissions were significantly reduced for young people who transitioned from the ARMS clinic, the personality disorder clinic or the primary care service compared to those who presented directly with FEP.A significant proportion of young people with FEP initially attended another specialist youth mental health service, and importantly, they had much lower rates of hospital admission at the time of transition to FEP.

Childhood and adolescence are vulnerable periods for development of a depressive disorder, with potentially lifelong negative consequences. Research increasingly suggests that lifestyle practices, including diet, are an effective adjunct strategy for the management of poor mental health. Dietary improvements are now recommended as the first actionable step in the treatment of depression in adults. In young people, evidence is also suggestive of a link between diet and mental health. However, implementing dietary interventions in youth can be challenging owing to numerous barriers. This paper reviews the literature on the topic and proposes several strategies that could be used by mental health clinicians to address diet as part of their practice. [ Psychiatr Ann . 2022;52(2):56–61.]

Background Young people with social disability and severe and complex mental health problems have poor outcomes, frequently struggling with treatment access and engagement. Outcomes may be improved by enhancing care and providing targeted psychological or psychosocial intervention. Aims We aimed to test the hypothesis that adding social recovery therapy (SRT) to enhanced standard care (ESC) would improve social recovery compared with ESC alone. Method A pragmatic, assessor-masked, randomised controlled trial (PRODIGY: ISRCTN47998710) was conducted in three UK centres. Participants (n = 270) were aged 16–25 years, with persistent social disability, defined as under 30 hours of structured activity per week, social impairment for at least 6 months and severe and complex mental health problems. Participants were randomised to ESC alone or SRT plus ESC. SRT was an individual psychosocial therapy delivered over 9 months. The primary outcome was time spent in structured activity 15 months post-randomisation. Results We randomised 132 participants to SRT plus ESC and 138 to ESC alone. Mean weekly hours in structured activity at 15 months increased by 11.1 h for SRT plus ESC (mean 22.4, s.d. = 21.4) and 16.6 h for ESC alone (mean 27.7, s.d. = 26.5). There was no significant difference between arms; treatment effect was −4.44 (95% CI −10.19 to 1.31, P = 0.13). Missingness was consistently greater in the ESC alone arm. Conclusions We found no evidence for the superiority of SRT as an adjunct to ESC. Participants in both arms made large, clinically significant improvements on all outcomes. When providing comprehensive evidence-based standard care, there are no additional gains by providing specialised SRT. Optimising standard care to ensure targeted delivery of existing interventions may further improve outcomes.

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.

Increased severity of neurological soft signs (NSS) in schizophrenia have been associated with abnormal brain morphology in cerebello-thalamo-cortical structures, but it is unclear whether similar structures underlie NSS prior to the onset of psychosis. The present study investigated the relationship between severity of NSS and grey matter volume (GMV) in individuals at ultra-high risk for psychosis (UHR) stratified for later conversion to psychosis. Structural T1-weighted MRI scans were obtained from 56 antipsychotic-naive UHR individuals and 35 healthy controls (HC). The UHR individuals had follow-up data (mean follow-up: 5.2 years) to ascertain clinical outcome. Using whole-brain voxel-based morphometry, the relationship between NSS and GMV at baseline was assessed in UHR, HC, as well as individuals who later transitioned (UHR-P, n = 25) and did not transition (UHR-NP, n = 31) to psychosis. NSS total and subscale scores except motor coordination were significantly higher in UHR compared to HC. Higher signs were also found in UHR-P, but not UHR-NP. Total NSS was not associated with GMV in the whole sample or in each group. However, in UHR-P individuals, greater deficits in sensory integration was associated with lower GMV in the left cerebellum, right insula, and right middle frontal gyrus. In conclusion, NSS are present in UHR individuals, particularly those who later transitioned to a psychotic disorder. While these signs show little overall variation with GMV, the association of sensory integration deficits with lower GMV in UHR-P suggests that certain brain areas may be implicated in the development of specific neurological abnormalities in the psychosis prodrome.

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.

Background No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group. Methods Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12-25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. Conclusion This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.

ObjectivesChildhood trauma is common and associated with mental ill health. While high rates of trauma are observed across individual disorder groups, there is evidence that trauma is associated with an admixture of affective, anxiety, and psychotic symptoms in adults. Given that both early onset of mental disorder and trauma exposure herald poor outcomes, it is important to examine trauma prevalence rates in youth mental health services and to determine whether this trauma-related clustering is present in help-seeking young people.MethodsWe used data from the Transitions Study, a longitudinal investigation of young people attending one of four headspace youth mental health services in Melbourne and Sydney, Australia between January 2011 and August 2012. Participants were 775 young people aged 12 to 25 (65.9% female; mean age = 18.3, SD = 3.2). Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Multinomial regression was used to assess whether reported childhood trauma was more strongly associated with the co-occurrence of depression, anxiety, mania, and psychosis symptoms than with any one in isolation.ResultsApproximately 84% of participants reported some form of abuse (emotional: 68%; physical: 32%; sexual: 22%) or neglect (emotional: 65%; physical: 46%) during childhood or adolescence. Exposure to multiple trauma types was common. Childhood trauma was significantly associated with each symptom domain (depression, mania, anxiety and psychosis). Childhood trauma was more strongly associated with the co-occurrence of these symptoms than with any one of these domains in isolation, such that trauma-exposed young people were more likely to experience increased symptom clustering than their non-exposed counterparts.ConclusionsChildhood trauma is pervasive in youth mental health services and associated with a heterogeneous symptom profile that cuts across traditional diagnostic boundaries.

Over a quarter of a century ago, the formulation of the "at risk mental state" and operational criteria to prospectively identify individuals at "clinical" or "ultra-high risk" (UHR) for psychosis created a global wave of research momentum aimed at predicting and preventing first-episode psychosis. A substantial number of randomized controlled trials (RCTs) were conducted to determine if transition to psychosis could be delayed or even prevented. The efficacy of a range of interventions was examined, with standard meta-analyses clearly indicating that these could at least delay transition for 1-2 years and that outcomes improve. Recently, network meta-analyses have attempted to identify the most effective intervention. These highlighted the fact that no one form of intervention is superior to the rest, a finding interpreted in such a way as to create doubts concerning the value of intervening. These doubts have been reinforced by a subsequent Cochrane review which judged the quality of the evidence as low or very low. Here, we report a narrative review of findings from RCTs and meta-analyses on the efficacy of interventions in UHR. We also critique the network meta-analyses and the Cochrane review, and indicate that many of the trials were of the highest possible quality for such research, and were published in top ranked psychiatry journals, which demand such quality. Although outcomes vary, and the UHR group is clearly heterogeneous, we highlight the clinical benefits of psychosocial treatment. The next generation of clinical trials seek to elucidate the optimal type, duration and sequence of interventions.

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.

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.

AIMS: Psychotic-like experiences (PLEs) are common in adolescents. Their persistence may confer increased susceptibility to psychotic disorder. The early evolution of transient to persistent PLEs is not well known. This study aimed to investigate the early persistence of PLEs (over 6-12 months) in a community sample of adolescents and examine baseline and longitudinal associations of early persistent PLEs. METHODS: Five hundred and ninety Year 10 students were administered the community assessment of psychic experiences (CAPE) to measure PLEs at baseline and at follow up 6-12 months later. Persistent PLEs were defined as those present at or above the 90th centile at both time points. Independent variables of depression, psychological distress and functioning were all measured at both baseline and follow up. Self-esteem, personality and suicidality were assessed at follow up. RESULTS: The study found 5.1% of participants had early persistent PLEs. Persistence was associated positively with depression and distress at both time points, neuroticism and openness at baseline and suicidality at follow up. Persistence was negatively associated with functioning at both time points, agreeableness at baseline and self-esteem at follow-up. Only depression remained significantly associated at both time points when accounting for other variables. Thus, depressive symptoms may account for changes in other domains and be a predictor of early PLEs persistence. CONCLUSIONS: These results reinforce the importance of monitoring and assessing PLEs in young people especially when associated with depression. Further research is required to investigate PLE persistence over longer periods with increased measurement intervals.

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.

Aim Phenomena within the psychosis continuum that varies in frequency/duration/intensity have been increasingly identified. Different terms describe these phenomena, however there is no standardization within the terminology. This review evaluated the definitions and assessment tools of seven terms - (i) 'psychotic experiences'; (ii) 'psychotic-like experiences'; (iii) 'psychotic-like symptoms'; (iv) 'attenuated psychotic symptoms'; (v) 'prodromal psychotic symptoms'; (vi) 'psychotic symptomatology'; and (vii) 'psychotic symptoms'. Methods EMBASE, MEDLINE, and CINAHL were searched during February-March 2019. Inclusion criteria included 1989-2019, full text, human, and English. Papers with no explicit definition or assessment tool, duplicates, conference abstracts, systematic reviews, meta-analyses, or no access were excluded. Results A total of 2238 papers were identified and of these, 627 were included. Definitions and assessment tools varied, but some trends were found. Psychotic experiences and psychotic-like experiences were transient and mild, found in the general population and those at-risk. Psychotic-like symptoms were subthreshold and among at-risk populations and non-psychotic mental disorders. Attenuated psychotic symptoms were subthreshold but associated with distress, risk, and help-seeking. Prodromal psychotic symptoms referred to the prodrome of psychotic disorders. Psychotic symptomatology included delusions and hallucinations within psychotic disorders. Psychotic symptoms was the broadest term, encompassing a range of populations but most commonly involving hallucinations, delusions, thought disorder, and disorganization. Discussion A model for conceptualizing the required terms is proposed and future directions needed to advance this field of research are discussed.

Background: NEURAPRO was a multicenter, double-blind, randomised, placebo-controlled trial RCT of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) ('fish oil') therapy provided for 6 months in individuals at ultra-high risk (UHR) for psychotic disorders, followed by an additional 6-month follow-up period. The study was conducted in 10 specialized early psychosis treatment services in Australia, Asia, and Europe, in 304 participants who received either n-3 PUFA together with cognitive behavioral case management (CBCM) or placebo with CBCM. In the intention to treat analysis, NEURAPRO failed to replicate findings of a previous single-center study. Although the RCT design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil RCTs, since the test agent is not only present in the intervention group but n-3 PUFA are present in the diet and in the body tissue of all participants, potentially influencing outcomes. Methods: We conducted a biomarker analysis in NEURAPRO participants to determine if n-3 PUFA (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; n-3 index; EPA+DHA) levels measured in erythrocyte membranes at baseline and at month 6 (end-of supplementation) predicted clinical outcomes 6 and 12 months after study entry in the participants irrespective of their original treatment group allocation in the trial. Findings: Of the 304 participants, 285 (94%) had biomarker data at baseline and 218 (72%) participants had biomarker data at baseline and a subsequent time point (209 at month 6; 9 at transition to psychosis). Increases of the n-3 index, EPA and DHA consistently predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of the n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio (95%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). The transition to psychosis rate was lower than expected in this study (5.0% at month 6; 10.1% at month 12). No association was observed between n-3 PUFA measures and transition to psychosis. Interpretation: These data suggest that n-3 PUFA can exert protective and therapeutic effects in UHR individuals. This finding may have implications for early intervention and clinical treatment guidelines since n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services. Trial Registration: The trial was registered at the Australia and New Zealand Clinical Trials Registry (ID 12608000475347). Funding Statement: This work was supported by grant 07TGF-1102 from the Stanley Medical Research Institute, grant 566529 from the NHMRC Australia Program (Drs McGorry, Hickie, and Yung, and Amminger), and a grant from the Colonial Foundation. Drs Amminger and Yung were supported by NHMRC Senior Research Fellowships 1080963 and 566593, respectively; and Dr Nelson was supported by NHMRC Career Development Fellowship 1027532. Dr McGorry was supported by Senior Principal Research Fellowship 1060996 from the National Health and Medical Research Council of Australia (NHMRC). Declaration of Interests: Drs Amminger, Hickie, Yung, and Nelson have received National Health and Medical Research Council (NHMRC) funding. Dr McGorry reported receiving grant funding from National Alliance for Research on Schizophrenia and Depression and unrestricted research funding from AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, and Novartis, as well as honoraria for educational activities with AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, Bristol-Myers Squibb, Roche, and the Lundbeck Institute. No other conflicts were reported. Ethics Approval Statement: The National Health and Medical Research Council of Australia (NHMRC) National Statement on Human Research was adhered to and appropriate ethical approval was obtained by each site (Melbourne, Australia: Melbourne Health Research Ethics Committee; Sydney, Australia: Sydney South West Area Health Service Ethics Review Committee; Basel, Switzerland: Ethics Commission for Basel; Zurich, Switzerland: Cantonal Ethics Commission Zurich; Jena, Germany: University Clinic Jena Ethics Commission; Copenhagen, Denmark: Capital Region Research Ethics Committee; Hong Kong: Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster; Vienna, Austria: Medical University of Vienna Ethics Commission; Singapore: National Healthcare Group Domain Specific Review Board; and Amsterdam, the Netherlands: Academic Medical Centre Medical Ethics Committee). Written informed consent was obtained for those younger than 17 years, parental or guardian consent was sought. Participants received financial compensation.

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.

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.

Background: \ud Early warning signs monitoring by service users with schizophrenia has shown promise in preventing relapse but the quality of evidence is low. We aimed to establish the feasibility of undertaking a definitive randomised controlled trial to determine the effectiveness of a blended digital intervention for relapse prevention in schizophrenia.\ud \ud Methods: \ud This multicentre, feasibility, cluster randomised controlled trial aimed to compare Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) with treatment as usual in community mental health services (CMHS) in Glasgow and Melbourne. CMHS were the unit of randomisation, selected on the basis of those that probably had five or more care coordinators willing to participate. Participants were eligible if they were older than 16 years, had a schizophrenia or related diagnosis confirmed via case records, were able to provide informed consent, had contact with CMHS, and had had a relapse within the previous 2 years. Participants were randomised within stratified clusters to EMPOWER or to continue their usual approach to care. EMPOWER blended a smartphone for active monitoring of early warning signs with peer support to promote self-management and clinical triage to promote access to relapse prevention. Main outcomes were feasibility, acceptability, usability, and safety, which was assessed through face-to-face interviews. App usage was assessed via the smartphone and self-report. Primary end point was 12 months. Participants, research assistants and other team members involved in delivering the intervention were not masked to treatment conditions. Assessment of relapse was done by an independent adjudication panel masked to randomisation group. The study is registered at ISRCTN (99559262).\ud \ud Findings: \ud We identified and randomised eight CMHS (six in Glasgow and two in Melbourne) comprising 47 care coordinators. We recruited 86 service users between Jan 19 and Aug 8, 2018; 73 were randomised (42 [58%] to EMPOWER and 31 [42%] to treatment as usual). There were 37 (51%) men and 36 (49%) women. At 12 months, main outcomes were collected for 32 (76%) of service users in the EMPOWER group and 30 (97%) of service users in the treatment as usual group. Of those randomised to EMPOWER, 30 (71%) met our a priori criterion of more than 33% adherence to daily monitoring that assumed feasibility. Median time to discontinuation of these participants was 31·5 weeks (SD 14·5). There were 29 adverse events in the EMPOWER group and 25 adverse events in the treatment as usual group. There were 13 app-related adverse events, affecting 11 people, one of which was serious. Fear of relapse was lower in the EMPOWER group than in the treatment as usual group at 12 months (mean difference –7·53 (95% CI –14·45 to 0·60; Cohen's d –0·53).\ud \ud Interpretation: \ud A trial of digital technology to monitor early warning signs blended with peer support and clinical triage to detect and prevent relapse appears to be feasible, safe, and acceptable. A further main trial is merited.\ud \ud Funding: \ud UK National Institute for Health Research Health Technology Assessment programme and the Australian National Health and Medical Research Council.

Aim: Investigating biological processes in at-risk individuals may help elucidate the aetiological mechanisms underlying psychosis development, refine prediction models and improve intervention strategies. This study examined the associations between sleep disturbances, chronotype, depressive and psychotic symptoms in individuals at ultra-high risk for psychosis. Methods: A sample of 81 ultra-high risk patients completed clinical interviews and self-report assessments of chronotype and sleep during the Neurapro clinical trial. Mixed regression was used to investigate the cross-sectional associations between symptoms and sleep disturbances/chronotype. Results: Sleep disturbances were significantly associated with increased depressive and attenuated positive psychotic symptoms. Greater preference for eveningness was significantly associated with increased negative symptoms, but not with depressive or attenuated positive psychotic symptoms. Conclusion: Sleep disturbances and chronotype may impact the emerging psychopathology experienced by ultra-high risk individuals. Further, the preliminary relationship observed between greater preference for eveningness and negative symptoms offers a unique opportunity to treat negative symptoms through chronobiological approaches.

Background: Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition to a psychotic disorder. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data from three time-points, spanning an average of eight years.Methods: Participants (N=139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests.Results: The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (β=−0.12, 95% CI [−0.29, 0.05] for Vocabulary and β=−0.14, 95% CI [−0.33, 0.05] for Similarities). Conclusions: There was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. As the small sample of individuals who transitioned may have limited our ability to detect subtle differences, future studies with larger sample sizes are needed to explore potential differences in intelligence trajectories between UHR transition groups.

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.

OBJECTIVE: Emerging evidence suggests that handgrip strength (a proxy for muscular fitness) is associated with better cognitive performance in people with major depressive disorder (MDD). The underlying processes are unclear, although hippocampal volume (HCV) reductions and white matter hyperintensities (WMHs) have been implicated. Therefore, we investigated the associations between handgrip strength and various brain region volumes and WMHs in MDD and healthy controls (HCs). METHODS: This study is a cross-sectional analysis of handgrip strength and neuroimaging data from the UK Biobank. Generalized linear models were used to assess the relationship between grip strength and gray matter, white matter, total brain volume, left and right hippocampus volume, and WMHs in MDD and HCs, adjusting for age, sex, education, and body weight. RESULTS: The sample included 527 people with MDD (54.3 ± 7.3 years, 37.2% male) and 1764 HCs (56.6 ± 7.2 years, 53% male). In MDD, stronger handgrip was significantly associated with increased left (coefficient ± SE = 108.1 ± 27.6, t = 3.92) and right (76.8 ± 30.4, t = 2.53) HCV. In HCs, only right HCV related to handgrip strength (44.8 ± 18.1, t = 2.47). Interaction analyses found stronger associations between grip strength and HCV in MDD compared with HCs, for both hippocampal regions. Stronger handgrip was associated with reduced WMHs in people with MDD (-0.24 ± 0.07, t = -3.24) and HCs (-0.11 ± 0.04, t = -2.47). Maximal handgrip strength was not associated with gray matter, white matter, or total brain volumes in either group. CONCLUSIONS: Stronger grip strength is associated with greater left and right HCV and reduced WMHs in MDD. Future research should investigate directionality and consider if interventions targeting strength/muscular fitness can improve brain health and reduce the neurocognitive abnormalities associated with MDD. ispartof: PSYCHOSOMATIC MEDICINE vol:82 issue:1 pages:39-46 ispartof: location:United States status: published

BackgroundIn the 1990s criteria were developed to detect individuals at high and imminent risk of developing a psychotic disorder. These are known as the at risk mental state, ultra high risk or clinical high risk criteria. Individuals meeting these criteria are symptomatic and help-seeking. Services for such individuals are now found worldwide. Recently Psychological Medicine published two articles that criticise these services and suggest that they should be dismantled or restructured. One paper also provides recommendations on how ARMS services should be operate.MethodsIn this paper we draw on the existing literature in the field and present the perspective of some ARMS clinicians and researchers.ResultsMany of the critics' arguments are refuted. Most of the recommendations included in the Moritz et al. paper are already occurring.ConclusionsARMS services provide management of current problems, treatment to reduce risk of onset of psychotic disorder and monitoring of mental state, including attenuated psychotic symptoms. These symptoms are associated with a range of poor outcomes. It is important to assess them and track their trajectory over time. A new approach to detection of ARMS individuals can be considered that harnesses broad youth mental health services, such as headspace in Australia, Jigsaw in Ireland and ACCESS Open Minds in Canada. Attention should also be paid to the physical health of ARMS individuals. Far from needing to be dismantled we feel that the ARMS approach has much to offer to improve the health of young people.

Aims: Psychotic-like experiences (PLE) are sub-threshold, non-clinical forms of psychosis which can place an individual at greater risk of development of a psychotic disorder. Subtypes of PLE have also been shown to exist (bizarre experiences, persecutory ideation, perceptual abnormalities and magical thinking). Perceived stress relates to how two individuals may deal with the same objectively stressful event in different ways. The objective of our study was to investigate the extent to which perceived stress is associated with PLE in a community sample of adolescents, whether certain subtypes of PLE correlate more with perceived stress than others and to explore the role of depression with these associations. Methods: A total of 655 students completed the community assessment of psychic experiences (CAPE) and perceived stress scale (PSS). Pearson's correlation was used to investigate the relationship between PSS and CAPE and also between perceived stress and the four subtypes of PLE. Regression then explored the effect of perceived stress on PLE when accounting for depressive symptomatology. Results: Positive correlation was found between PSS and total CAPE (r = 0.405, P = 0.000). Positive significant correlation was also found between PSS and each subtype of PLE, with persecutory ideation correlating the strongest and magical thinking the least. Perceived stress was significantly associated with PLE even after adjusting for depression. Conclusions: We recommend that more regular screening of perceived stress in adolescent populations could lead to earlier recognition of PLE. Early treatment has shown to reduce rates of transition to psychosis, and so could benefit our adolescent community in the future.

IMPORTANCE The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.OBJECTIVE To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).DESIGN, SETTING, AND PARTICIPANTS In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.MAIN OUTCOMES AND MEASURES Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).RESULTS Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (rho = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (rho = 0.43; 95% CI, 0.20 to 0.61; P = .001).CONCLUSIONS AND RELEVANCE This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.Question How are brain morphometric features associated with later psychosis conversion in individuals at clinical high risk (CHR) for developing psychosis?Findings In this case-control study including 3169 participants, lower cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in individuals at CHR in a manner highly consistent with thinner cortex in individuals with established psychosis. Regions that displayed lower cortical thickness in individuals at CHR who later developed a psychotic disorder additionally displayed abnormal associations with age.Meaning In this study, CHR status and later transition to psychosis was robustly associated with lower cortical thickness; abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in individuals at CHR, including pruning and myelination.This case-control study investigates baseline structural magnetic resonance imaging (MRI) differences between individuals at clinical high risk and healthy controls as well as between participants at clinical high risk who later developed a psychotic disorder and those who did not.

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.