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Background:After a first episode of psychosis, cognitive impairments present an important barrier to successful (re-)entry into work and education. We assessed whether cognitive remediation (CR) as an add-on to Individual Placement and Support (IPS) can improve participation in regular employment and education.Method:Participants with early psychosis (N = 73) were randomly assigned to receive IPS supplemented with computerized CR, or IPS plus an active control intervention (computer games). The primary outcome was the number of hours spent in competitive employment or regular education, which was assessed every month during the 18-month study period. Secondary outcomes included employment rate, cognitive functioning, mental health (assessed at baseline, 6 and 18 months), and job duration (assessed after 18 months). Both patients and assessors were blind to treatment.Results:Participants receiving IPS + CR showed greater improvement of competitive employment over time in terms of hours worked (during follow-up period: 38.5 vs. 19.6 h, B = 2.94; Wald χ2 = 5.39; P = .02) and employment rate (at T2: 62.1% vs. 25.9%, χ 2 = 7.39; df = 1; P = .008), compared with the IPS + control group, particularly in the longer term. The number of hours spent in regular education was lower in the IPS + CR group, with more participants having ended education for a positive reason. There was a significant beneficial effect of adjunctive CR for executive functioning, subjective cognitive functioning, and empowerment.Conclusions:Augmenting IPS with CR has a significant impact on competitive employment in people with early psychosis, with beneficial effects being more pronounced after 18 months.

BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.MethodsWe analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.ResultsThe impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).ConclusionsThe results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

Introduction: In patients with psychotic disorders, both tobacco smoking and deficits in social cognition and social functioning are highly prevalent. However, little is known about their relationship in psychosis. The authors sought to evaluate the multi-cross-sectional and longitudinal associations between tobacco smoking, social cognition and social functioning in a large prospective study.Methods: This study was performed within the Genetic Risk and Outcome of Psychosis (GROUP) Study, a cohort study conducted in patients with non-affective psychosis (N = 1074), their unaffected siblings (N = 1047) and healthy controls (N = 549). At baseline, three years and six years of follow-up, data on tobacco smoking (using the Composite International Diagnostic Review), social cognition (emotion processing and theory of mind) and social functioning were collected. To assess associations between tobacco smoking and social cognition or social functioning, multivariate linear mixed-effects models and multiple linear regression models were used. Bon-ferroni correction for multiple testing was applied.Results: A significant positive association was found between smoking and emotion processing (as part of social cognition) in the patient group (estimate = 1.96, SE = 0.6, p = 0.003). However, smoking was significantly negatively associated with participating in pro-social activities compared with non-smoking (estimate =-2.55, SE = 0.9, p = 0.004). Change in smoking behaviour was not associated with social cognition or social functioning in the longitudinal analyses.Conclusion: Findings indicate that smoking patients with a non-affective psychotic disorder slightly outperformed their non-smoking peers on a task on social cognition, but participated less in pro-social activities. Commencement or cessation of smoking was not related to social cognition or functioning.

Key Points Question Are clinical and demographic factors associated with brain glutamate or glutamate plus glutamine (Glx) levels in schizophrenia? Findings In this mega-analysis of 1251 patients with schizophrenia and 1197 healthy volunteers, medial frontal cortex glutamatergic metabolite levels were lower in patients and negatively associated with the dose of antipsychotic medication, although a reduction in glutamate levels with age was not accelerated in patients with schizophrenia compared with healthy individuals. Higher medial frontal cortex and medial temporal lobe glutamate levels were associated with more severe symptoms in patients with schizophrenia. Meaning Lower brain glutamate levels may be associated with antipsychotic exposure rather than with greater age-related decline, whereas higher glutamate levels may serve as a biomarker of illness severity in patients with schizophrenia., Importance Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P, This mega-analysis assesses whether age, symptom severity, level of functioning, and antipsychotic treatment are associated with glutamate or glutamatergic metabolite levels measured with proton magnetic resonance spectroscopy in the medial frontal cortex or medial temporal lobe of patients with schizophrenia.

Cognitive performance at illness onset may predict outcomes in first-episode psychosis (FEP), and the change in cognition may associate with clinical changes. Cognitive testing was administered to fifty-four FEP participants two months after entering treatment and to thirty-nine participants after one year. We investigated whether baseline cognition predicted one-year outcomes beyond positive, negative, and affective symptoms and whether the trajectory of cognition associated with clinical change. Baseline overall neurocognitive performance predicted the one-year social and occupational level, occupational status, and maintaining of life goals. The domain of processing speed associated with the one-year remission, occupational status, and maintaining of life goals. Baseline social cognition associated with occupational status a year later and the need for hospital treatment during the first year after FEP. Most of the associations were retained beyond baseline positive and affective symptom levels, but when accounting for negative symptoms, cognition no longer predicted one-year outcomes, highlighting how negative symptoms overlap with cognition. The trajectory of neurocognitive performance over the year did not associate with changes in symptoms or functioning. Cognitive testing at the beginning of treatment provided information on the one-year outcome in FEP beyond positive and affective symptom levels. In particular, the domains of processing speed and social cognition could be targets for interventions that aim to improve the outcome after FEP.

To tackle the phenotypic heterogeneity of schizophrenia, data-driven methods are often applied to identify subtypes of its symptoms and cognitive deficits. However, a systematic review on this topic is lacking. The objective of this review was to summarize the evidence obtained from longitudinal and cross-sectional data-driven studies in positive and negative symptoms and cognitive deficits in patients with schizophrenia spectrum disorders, their unaffected siblings and healthy controls or individuals from general population. Additionally, we aimed to highlight methodological gaps across studies and point out future directions to optimize the translatability of evidence from data-driven studies. A systematic review was performed through searching PsycINFO, PubMed, PsycTESTS, PsycARTICLES, SCOPUS, EMBASE and Web of Science electronic databases. Both longitudinal and cross-sectional studies published from 2008 to 2019, which reported at least two statistically derived clusters or trajectories were included. Two reviewers independently screened and extracted the data. In this review, 53 studies (19 longitudinal and 34 cross-sectional) that conducted among 17,822 patients, 8729 unaffected siblings and 5520 controls or general population were included. Most longitudinal studies found four trajectories that characterized by stability, progressive deterioration, relapsing and progressive amelioration of symptoms and cognitive function. Cross-sectional studies commonly identified three clusters with low, intermediate (mixed) and high psychotic symptoms and cognitive profiles. Moreover, identified subgroups were predicted by numerous genetic, sociodemographic and clinical factors. Our findings indicate that schizophrenia symptoms and cognitive deficits are heterogeneous, although methodological limitations across studies are observed. Identified clusters and trajectories along with their predictors may be used to base the implementation of personalized treatment and develop a risk prediction model for high-risk individuals with prodromal symptoms.

Purpose of reviewArguably, the strongest evidence of an environmental contribution to the cause of psychosis is the increased risk for certain groups of migrants and ethnic minorities. This article summarizes findings published since 2016.Recent findingsTwo studies suggested that migration or minority status are proxies for exposure to an inferior social status. A study from Bologna, Italy, showed that the psychosis risk for internal migrants from Southern Italy was as much increased as that for international migrants. A report from New Zealand reported a higher risk for Maoris than for the remainder of the population.Furthermore, a Danish investigation showed that own-group ethnic density of the neighbourhood at age 15 strongly modified the psychosis risk at adult age. This rules out differential mobility during the prodromal phase as an explanation for the ethnic density effect. Preliminary evidence suggests that the psychotogenic effect of migration may be mediated by elevated dopamine in the striatum.SummaryAn increasing body of evidence suggests that the higher psychosis risk for certain migrant or ethnic minority groups is due to an inferior social status. Neuroimaging of the dopamine system appears to be a promising avenue for research into pathogenesis.

Objective To provide an update on the evidence base for the nature of the relationship between negative symptoms and depressive features in people with schizophrenia, and propose new models that reflect their complex relationship. Method A systematic review following PRISMA guidelines. A total of 2210 articles were identified from EMBASE, PsychInfo and MEDLINE, and further two articles were hand-searched from references. Twenty-seven met inclusion criteria and were included in the review. Results In schizophrenia, primary evidence suggests symptoms of low mood, suicidal ideation and pessimism have more specificity for depression whereas alogia and blunted affect may have more specificity as negative symptoms. Anhedonia, anergia and avolition may be common to both. Conclusion It may be possible to further distinguish depressive features from negative symptoms in schizophrenia when detailed phenomenology is considered. However, in a proposed dimensional model, these two domains continue to share certain phenomena, highlighting their close relationship.

Background: Historically, research investigating neural correlates of mentalizing deficits in schizophrenia has focused on patients who have been ill for several years with lengthy exposure to medication. Little is known about the neural and behavioural presentations of theory-of-mind deficits in schizophrenia, shortly after the first episode of psychosis. \ud \ud Methods: We investigated social cognition in seventeen recently diagnosed first-episode schizophrenia (FES) patients with little or no exposure to antipsychotic medication and 1:1 matched healthy controls. We recorded behavioural and neural responses to the Animated Triangles Task (ATT), which is a non-verbal validated mentalizing task that measures the ascription of intentionality to the movements of objects. \ud \ud Results: FES patients under-interpreted social cues and over-interpreted non-social cues. These effects were influenced by current intelligence (IQ). Control group and FES neural responses replicated earlier findings in healthy adults. However, a region of anterior medial prefrontal cortex (amPFC) of FES patients showed a different response pattern to that of controls. Unlike healthy controls, patients increased activity in this social cognition region while studying ‘random’ movements of shapes, as compared to the study of movements normally interpreted as ‘intentional’. \ud \ud Conclusions: Mentalizing deficits in FES consists of hypo- and hyper-mentalizing. The neural pattern of FES patients is consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming. Overall, results demonstrate complexities of theory of mind deficits in schizophrenia that should be considered when offering social cognitive training programs.

Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes.Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP.Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019.Interventions: Monthly augmentation with 120 000 IU of cholecalciferol or placebo.Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline.Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations.Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies.Trial Registration: isrctn.org Identifier: ISRCTN12424842.

BackgroundVerbal learning (VL) and fluency (VF) are prominent cognitive deficits in psychosis, of which the precise neuroanatomical contributions are not fully understood. We investigated the arcuate fasciculus (AF) and its associated cortical regions to identify structural abnormalities contributing to these verbal impairments in early stages of psychotic illness.MethodsTwenty-six individuals with recent-onset psychosis and 27 healthy controls underwent cognitive testing (MATRICS Consensus Cognitive Battery) and structural/diffusion-weighted MRI. Bilaterally, AF anisotropy and cortical thickness, surface area and volume of seven cortical regions were investigated in relation to VL and VF performance in both groups.ResultsReduced right superior temporal gyrus surface area and volume related to better VF in controls. In psychosis, greater right pars opercularis volume and reduced left lateralization of this region related to better VL, while greater right long AF fractional anisotropy and right pars orbitalis volume related to better VF, these findings not present in controls. Psychosis had reduced right pars orbitalis thickness compared to controls.ConclusionAnatomical substrates for normal processing of VL and VF appear altered in recent-onset psychosis. A possible aberrant role of the right hemisphere arcuate fasciculus and fronto-temporal cortical regions in psychosis may contribute to deficits in VL and VF.

Background\ud Polygenic risk scores (PRSs) have successfully summarized genome-wide effects of genetic variants in schizophrenia with significant predictive power. In a clinical sample of first-episode psychosis (FEP) patients, we estimated the ability of PRSs to discriminate case-control status and to predict the development of schizophrenia as opposed to other psychoses.\ud \ud Methods\ud The sample (445 case and 265 control subjects) was genotyped on the Illumina HumanCore Exome BeadChip with an additional 828 control subjects of African ancestry genotyped on the Illumina Multi-Ethnic Genotyping Array. To calculate PRSs, we used the results from the latest Psychiatric Genomics Consortium schizophrenia meta-analysis. We examined the association of PRSs with case-control status and with schizophrenia versus other psychoses in European and African ancestry FEP patients and in a second sample of 248 case subjects with chronic psychosis.\ud \ud Results\ud PRS had good discriminative ability of case-control status in FEP European ancestry individuals (9.4% of the variance explained, p < 10−6), but lower in individuals of African ancestry (R2 = 1.1%, p = .004). Furthermore, PRS distinguished European ancestry case subjects who went on to acquire a schizophrenia diagnosis from those who developed other psychotic disorders (R2 = 9.2%, p = .002).\ud \ud Conclusions\ud PRS was a powerful predictor of case-control status in a European sample of patients with FEP, even though a large proportion did not have an established diagnosis of schizophrenia at the time of assessment. PRS was significantly different between those case subjects who developed schizophrenia from those who did not, although the discriminative accuracy may not yet be sufficient for clinical utility in FEP.

Aim: Most studies on the determinants of psychosocial functioning in first-episode psychosis used few predictors. This study examines the effects of multiple cognitive domains and multiple symptoms on psychosocial functioning.Methods: A total of 162 patients with a first-episode psychosis were assessed within 3 months after referral to an early psychosis treatment department. Four psychopathological subdomains (positive and negative symptoms, depression and anxiety) and five subdomains of psychosocial functioning (work/study, relationships, self-care, disturbing behaviour and general psychosocial functioning) were measured. Neurocognitive and social cognitive factors were identified through principal component analyses (PCA) of a 15-measure cognitive battery. Stepwise backward regression models were computed to identify the determinants of psychosocial functioning.Results: The three neurocognitive and four social cognitive factors identified through PCA were largely independent of psychopathology. The strongest associations were between cognitive factors and anxiety. Higher levels of negative symptoms, poor general neurocognition and poor general social cognition showed strongest associations with impaired psychosocial functioning, followed by low verbal processing speed and low emotion processing speed. Together, these factors accounted for 39.4% of the variance in psychosocial functioning.Conclusions: The results suggest that negative symptoms, impaired neurocognition and poor social cognition are related to psychosocial problems in patients with first-episode psychosis. None of the affective or positive symptoms had a marked impact on psychosocial functioning.

Clinical services for the early detection of individuals at clinical high risk of psychosis, such as Outreach and Support in South-London (OASIS), have been successful in providing psychological intervention and psychosocial support to young people experiencing emerging signs of serious mental disorders. Despite this, several studies have repeatedly shown that vocational and functional recovery in the clinical high risk for psychosis population is still low. This study aimed at evaluating the presence and nature of educational and employment focused interventions within the OASIS service, in order to inform research and clinical interventions aimed at supporting young people with early signs of psychosis on their path to vocational recovery. The specific objectives were to compare current practice i) to standards defined by the National Institute of Care Excellence guidelines; and ii) to principles defined by Individual Placement and Support (IPS). Nine standards of practice were derived. The OASIS caseload electronic records entered between January 2015 and January 2017 were manually screened. Data collected include sociodemographic, assessment of employment and educational status and support needs, interventions received, contacts with schools, employers and external vocational providers, employment, and educational status. Standards were considered as "met" if they were met for at least 90% of clients. Results suggest that, two out of nine standards were met while the remaining standards were only partially met. In particular, support provided was always focused on competitive employment and mainstream education and support was always based on people's interest. Implications for clinical and research practice are discussed. ispartof: FRONTIERS IN PSYCHIATRY vol:10 ispartof: location:Switzerland status: published

BackgroundLower intelligence quotient (IQ) has frequently been reported in patients with schizophrenia. However, it is unclear whether IQ declines (further) after illness onset and what the familial contribution is to this change. Therefore, we investigate IQ changes during the course of illness in patients with non-affective psychosis, their siblings and controls.MethodsData are part of the longitudinal Genetic Risk and Outcome of Psychosis (GROUP) study in the Netherlands and Belgium. Participants underwent three measurements, each approximately 3 years apart. A total of 1022 patients with non-affective psychosis [illness duration: 4.34 (s.d.= 4.50) years], 977 of their siblings, and 565 controls had at least one measure of IQ (estimated from four subtests of the WAIS-III).ResultsAt baseline, IQ was significantly lower in patients (IQ = 97.8) and siblings (IQ = 108.2;p< 0.0001) than in controls (IQ = 113.0;p< 0.0001), and in patients as compared with siblings (p< 0.0001). Over time, IQ increased in all groups. In siblings, improvement in IQ was significantly more pronounced (+0.7 points/year) than in patients (+0.5 points/year;p< 0.0001) and controls (+0.3 points/year;p< 0.0001). IQ increase was not significantly correlated with improvement in (sub)clinical outcome in any of the groups.ConclusionsDuring the first 10 years of the illness, IQ increases to a similar (and subtle) extent in a relatively high-functioning group of schizophrenia patients and controls, despite the lower IQ in patients at baseline. In addition, the siblings’ IQ was intermediate at baseline, but over time the increase in IQ was more pronounced.

AIMS: Theory of Mind (ToM) is often impaired in early and chronic phases of psychosis and it is often suggested that poor ToM is a trait vulnerability for psychosis. The aim of this study was to examine in an adolescent sample whether childhood ToM abilities can predict psychotic experiences over a period of six years and whether this is mediated by social functioning. To examine whether ToM is a specific predictor for psychosis, symptoms of depression and anxiety were also examined.MATERIALS AND METHODS: A baseline case-control sample (T0: age 7-8 years) with and without auditory vocal hallucinations (AVH) in the general population was assessed after five years (T1: age 12-13 years) on ToM ability (ToM Storybook Frank), and after eleven years (T2: age 18-19 years) on psychotic experiences (Community Assessment of Psychic Experiences; CAPE), depressive and anxiety symptoms (Depression Anxiety and Stress Scale; DASS-21), and social functioning (Groningen Questionnaire on Social Behaviour; GSVG-45). Analyses were conducted on a subsample of 157 adolescents aged 18-19 years (T2) who had data available on ToM ability at T1.RESULTS: ToM at T1 was not predictive of psychotic experiences after six years (from age 12-13 to age 18-19) and social functioning was also not a mediator. ToM was not associated with psychopathology in general (depressive and anxiety symptoms) over six years (from age 12-13 to age 18-19).CONCLUSIONS: The current study found no evidence for a longitudinal association between ToM ability and psychotic experiences, social functioning, and symptoms of depression and anxiety, in adolescence.

IntroductionSpecialised early intervention services have demonstrated improved outcomes in first-episode psychosis (FEP); however, clinical gains may not be sustained after patients are transferred to regular care. Moreover, many patients with FEP remain socially isolated with poor functional outcomes. To address this, our multidisciplinary team has developed a moderated online social media therapy (HORYZONS) designed to enhance social functioning and maintain clinical gains from specialist FEP services. HORYZONS merges: (1) peer-to-peer social networking; (2) tailored therapeutic interventions; (3) expert and peer-moderation; and (4) new models of psychological therapy (strengths and mindfulness-based interventions) targeting social functioning. The aim of this trial is to determine whether following 2 years of specialised support and 18-month online social media-based intervention (HORYZONS) is superior to 18 months of regular care.Methods and analysisThis study is a single-blind randomised controlled trial. The treatment conditions include HORYZONS plus treatment as usual (TAU) or TAU alone. We recruited 170 young people with FEP, aged 16–27 years, in clinical remission and nearing discharge from Early Psychosis Prevention and Intervention Centre, Melbourne. The study includes four assessment time points, namely, baseline, 6-month, 12-month and 18-month follow-up. The study is due for completion in July 2018 and included a 40-month recruitment period and an 18-month treatment phase. The primary outcome is social functioning at 18 months. Secondary outcome measures include rate of hospital admissions, cost-effectiveness, vocational status, depression, social support, loneliness, self-esteem, self-efficacy, anxiety, psychological well-being, satisfaction with life, quality of life, positive and negative psychotic symptoms and substance use. Social functioning will be also assessed in real time through our Smartphone Ecological Momentary Assessment tool.Ethics and disseminationMelbourne Health Human Research Ethics Committee (2013.146) provided ethics approval for this study. Findings will be made available through scientific journals and forums and to the public via social media and the Orygen website.Trial registration numberACTRN12614000009617; Pre-results.

The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We undertook a hypothesis-driven proteomic analysis of the complement signalling pathway (n=29 proteins) using Data Independent Acquisition. Participants were recruited from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12, among individuals who first reported psychotic experiences (PEs) at age 18 (n=64), were compared with age-matched controls (n=67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, C5↑).Using the same methods, we examined participants with Persistent Psychotic Experiences (PPE) at both age 12 and age 18 (n=38) compared to age-matched controls who only experienced PEs at age 12 (n=38). Here, we observed that five of 29 targeted complement proteins were differentially expressed (C1RL↑, C2↑, C4BPB↑, C9↑, CFD↑). Finally, we undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 10 complement proteins including five that were altered in the same direction in individuals with either PE or PPE (C1R↑, CFH↑, C4BP↑, C5↑, C9↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence and persistence of psychotic experiences and that these changes may reflect exposure to stress.

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognosticmarkers in FEP. Combination of differentmarkers inMLmodels with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.

The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognosticmarkers in FEP. Combination of differentmarkers inMLmodels with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future.

Purpose of reviewArguably, the strongest evidence of an environmental contribution to the cause of psychosis is the increased risk for certain groups of migrants and ethnic minorities. This article summarizes findings published since 2016.Recent findingsTwo studies suggested that migration or minority status are proxies for exposure to an inferior social status. A study from Bologna, Italy, showed that the psychosis risk for internal migrants from Southern Italy was as much increased as that for international migrants. A report from New Zealand reported a higher risk for Maoris than for the remainder of the population.Furthermore, a Danish investigation showed that own-group ethnic density of the neighbourhood at age 15 strongly modified the psychosis risk at adult age. This rules out differential mobility during the prodromal phase as an explanation for the ethnic density effect. Preliminary evidence suggests that the psychotogenic effect of migration may be mediated by elevated dopamine in the striatum.SummaryAn increasing body of evidence suggests that the higher psychosis risk for certain migrant or ethnic minority groups is due to an inferior social status. Neuroimaging of the dopamine system appears to be a promising avenue for research into pathogenesis.

OBJECTIVES: Inflammation and the cytokine hypotheses have been proposed for schizophrenia. Several proinflammatory and anti-inflammatory cytokines have been studied in drug-naive, first-episode, and/or chronic schizophrenia patients. However, there were limited data on clinical stable outpatients reflecting daily routine. The aim of this study was to compare the serum levels of cytokines, including transforming growth factor-beta (TGF-beta), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha), between clinically stable patients with schizophrenia and healthy controls, as well as to examine the relationship between these inflammation parameters and clinical variables (positive and negative symptom severity and cognitive functions). METHODS: Thirty clinically stable outpatients with schizophrenia and 30 healthy controls with similar sex and age were included in this study. Serum IL-6, TGF-beta, and TNF-alpha levels were assessed by enzyme-linked immunosorbent assay (ELISA) and immunoenzyme microplate measurement, respectively. Illness severity was evaluated using the Positive and Negative Syndrome Scale (PANSS), and the cognitive functions of the participants were assessed using a broad neuropsychological test battery. RESULTS: The serum levels of IL-6 and TGF-beta were significantly higher in patients with schizophrenia compared to healthy controls (p = .048, p = .012). There was no significant difference between groups in terms of TNF-alpha levels (p = .726). Global impairment of cognitive functions was observed in the patient group compared to healthy controls, and PANSS scores and cognitive functions showed no correlation with cytokine levels (IL-6, TNF-alpha, and TGF-beta). CONCLUSIONS: The present study demonstrated an increased inflammatory response in clinically stable patients with schizophrenia compared to healthy controls. However, symptom severity and cognitive functions showed no correlation with cytokine levels. Further research studies are needed to clarify the effects of cytokine levels on schizophrenia symptomatology and etiopathogenesis.

Objective: To enable further understanding of how cognitive deficits and psychopathology impact psychosocial functioning in first-episode psychosis patients, we investigated how psychopathology and cognitive deficits are associated with psychosocial problems at baseline, and how these predict psychosocial functioning at 12 months follow-up. Also, we tested whether the effect of baseline psychopathology on psychosocial functioning decreases between baseline and 12 months and the effect of baseline cognition increases.Methods: Eight neurocognitive and four social cognitive subdomains and psychopathology (positive and negative symptoms, depression and anxiety) were assessed at baseline in 153 non-affective first-episode psychosis (FEP) patients. Psychosocial functioning (work/study, relationships, self-care, disturbing behavior and general psychosocial functioning) was assessed at baseline and 12 months. Spearman correlations were examined and backward regression models were computed to test our hypotheses.Results: At baseline, psychosocial functioning was associated strongest with positive and negative symptoms of all assessed clinical domains, followed by neurocognition and social cognition. In contrast, psychosocial functioning at 12 months was not predicted by psychotic symptoms, but rather by neurocognition, social cognition and depression. Change in social functioning in the first 12 months after baseline was predicted by positive and negative symptoms, but to a similar degree by neurocognition and social cognition.Conclusions: Whereas psychotic symptoms show marked impact on psychosocial functioning at illness onset, cognitive deficits appear to be more accurate longitudinal predictors of psychosocial problems and functional recovery in the early course of psychosis. (C) 2014 Published by Elsevier B.V.

Background Although widespread reduced white matter (WM) integrity is a consistent finding in cross-sectional diffusion tensor imaging (DTI) studies of schizophrenia, little is known about the course of these alterations. This study examined to what degree microstructural WM alterations display differential trajectories over time as a function of level of psychosis liability. Methods Two DTI scans with a 3-year time interval were acquired from 159 participants (55 patients with a psychotic disorder, 55 nonpsychotic siblings and 49 healthy controls) and processed with tract-based spatial statistics. The mean fractional anisotropy (FA) change over time was calculated. Main effects of group, as well as group × region interactions in the model of FA change were examined with multilevel (mixed-effects) models. Results Siblings revealed a significant mean FA decrease over time compared to controls (B = −0.004, P = .04), resulting in a significant sibling-control difference at follow-up (B = −0.007, P = .03). Patients did not show a significant change over time, but their mean FA was lower than controls both at baseline and at follow-up. A significant group × region interaction (χ2 = 105.4, P = .01) revealed group differences in FA change in the right cingulum, left posterior thalamic radiation, right retrolenticular part of the internal capsule, and the right posterior corona radiata. Conclusion Whole brain mean FA remained stable over a 3-year period in patients with psychotic disorder and declined over time in nonaffected siblings, so that at follow-up both groups had lower FA with respect to controls. The results suggest that liability for psychosis may involve a process of WM alterations.

Background:Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia.Methods:Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression.Results:Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance (P= 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P= 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition.Conclusions:Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia.

Objective: To examine the utility of the Community Assessment of Psychic Experiences (CAPE)-42, a self-report questionnaire, to improve detection of first-episode psychosis in new referrals to mental health services. Method: At first contact with mental health-care services patients were asked to complete the CAPE-42 and were then routinely diagnosed by a clinician. Standard diagnoses were obtained by means of the mini-Schedule for Clinical Assessment in Neuropsychiatry. Results: Of the 246 included patients, 26 (10.6%) were diagnosed with psychosis according to the mini-Schedule for Clinical Assessment in Neuropsychiatry. Only 10 of them were recognized by clinical routine, and 16 psychotic patients were not properly identified. Using an optimal cut-off of 50 on the frequency or distress dimension of the positive subscale of the CAPE-42 detected 14 of these misdiagnosed patients. The sensitivity of the CAPE-42 at this cut-off point was 77.5 and the specificity 70.5. Conclusion: Systematic screening of patients using a self-report questionnaire for psychotic symptoms improves routine detection of psychotic patients when they first come into contact with mental health services

Background The high rate of cannabis use among patients with first-episode psychosis (FEP), as well as the associated negative impact on illness course and treatment outcomes, underlines the need for effective interventions in these populations. However, to date, there have been few clinical treatment trials (of pharmacological or psychological interventions) that have specifically focused on addressing comorbid cannabis use among these patients. The aim of this paper is to describe the design of a study protocol for a randomized controlled trial in which the objective is to assess the efficacy of a specific cognitive behavioral therapy program for cannabis cessation in patients with FEP compared to standard treatment (psychoeducation). Methods/design This is a single-blind randomized study with 1 year of follow-up. Patients are to be randomly assigned to one of two treatments: (1) specific cognitive behavioral therapy for cannabis cessation composed of 1-hour sessions once a week for 16 weeks, in addition to pharmacological treatment scheduled by the psychiatrist, or (2) a control group (psychoeducation + pharmacological treatment) following the same format as the experimental group. Participants in both groups will be evaluated at baseline (pre-treatment), at 16 weeks (post-treatment), and at 3 and 6 months and 1 year of follow-up. The primary outcome will be that patients in the experimental group will have greater cannabis cessation than patients in the control group at post-treatment. The secondary outcome will be that the experimental group will have better clinical and functional outcomes than the control group. Discussion This study provides the description of a clinical trial design based on specific cognitive behavioral therapy for cannabis cessation in FEP patients, aiming to improve clinical and functional outcome, as well as tackling the addictive disorder. Trial registration NCT02319746 ClinicalTrials.gov Identifier. ClinicalTrials.gov Protocol and Results Registration System (PRS) Receipt Release Date: 15 December 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1507-x) contains supplementary material, which is available to authorized users.

This study aims to compare the suicide risk over the past decade following recent onset psychosis to findings from the eighties and nineties in the same catchment area and to identify predictors of suicide in the context of the Psychosis Recent Onset Groningen-Survey (PROGR-S). A medical file search was carried out to determine the current status of all patients admitted between 2000 and 2009. The suicide rate was compared with a study executed in 1973-1988 in the same catchment area. Predictors of suicide were investigated using Cox regression. The status of 424 of the 614 patients was known in July 2014. Suicide occurred in 2.4% of patients with psychosis disorders (n = 10; mean follow-up 5.6 years); 6 out of 10 suicides took place within two years. Within two decades, the suicide rate dropped from 11% (follow-up 15 years, 8.5% after 5 years) to 2.4%. The Standardized Mortality Rate (SMR) of suicides compared with the general population was 41.6. A higher age was the only significant predictor for suicide. Neuroticism, living situation, disorganized and negative symptoms, and passive coping style all showed a trend for significance. A significant reduction in the suicide rate was found for people with psychosis over the past decades. Given the high SMR, suicide research should be given the highest priority. Identifying predictors may contribute to further reduction of suicide among patients with psychosis.

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1-and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFa, CXCL1, CCL7, IFN-alpha 2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum lan association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.evel of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate

BackgroundHippocampal pathology has been proposed to underlie clinical, functional and cognitive impairments in schizophrenia. The hippocampus is a highly plastic brain region; examining change in volume, or change bilaterally, over time, can advance understanding of the substrate of recovery in psychosis.MethodMagnetic resonance imaging and outcome data were collected at baseline and 6-year follow-up in 42 first-episode psychosis subjects and 32 matched controls, to investigate whether poorer outcomes are associated with loss of global matter and hippocampal volumes. Bilateral hippocampal increase (BHI) over time, as a marker of hippocampal plasticity was hypothesized to be associated with better outcomes. Regression analyses were performed on: (i) clinical and functional outcomes with grey matter volume change and BHI as predictor variables; and (ii) cognitive outcome with BHI as predictor.ResultsBHI was present in 29% of psychosis participants. There was no significant grey matter loss over time in either patient or control groups. Less severe illness course and lesser symptom severity were associated with BHI, but not with grey matter change. Employment and global function were associated with BHI and with less grey matter loss. Superior delayed verbal recall was also associated with BHI.ConclusionsBHI occurs in a minority of patients following their first psychotic episode and is associated with good outcome across clinical, functional and cognitive domains.

Background: Longer duration of untreated psychosis (DUP) is associated with poorer outcome in terms of positive symptoms, relapse rate, and time to remission. In contrast, the association with negative symptoms is less consistent. Aims: The study had three aims. First, to arrive at a more precise estimate of the correlation between DUP and negative symptoms than previous reviews, by substantially increasing the amount of available data. Second, to see whether the strength of this correlation attenuated over longer follow-up intervals. Third, to determine whether there is a relationship between DUP and changes in negative symptoms. Method: Relevant databases were searched for studies published between December 1992 and March 2009 that reported data on DUP and negative symptoms. We obtained individual patient data where possible and calculated summary correlations between DUP and negative symptoms for each study at baseline, short and long-term follow-up. We used multilevel regression analysis to examine whether the effect of DUP on negative symptoms was the greatest in the early stages of illness. Results: We included 28 non-overlapping studies from the 402 papers detected by the search strategy. After contacting the authors we obtained individual patient data from 16 of these studies involving 3339 participants. The mean DUP was 61.4 weeks (SD = 132.7, median DUP = 12.0). Shorter DUP was significantly associated with less severe negative symptoms at baseline and also at short (1-2 years) and longer term follow-up (5-8 years) (r = 0.117, 0.180 and 0.202 respectively, p

ObjectiveTreatment in the ultra-high risk stage for a psychotic episode is critical to the course of symptoms. Markers for the development of psychosis have been studied, to optimize the detection of people at risk of psychosis. One possible marker for the transition to psychosis is social cognition. To estimate effect sizes for social cognition based on a quantitative integration of the published evidence, we conducted a meta-analysis of social cognitive performance in people at ultra high risk (UHR).MethodsA literature search (1970-July 2015) was performed in PubMed, PsychINFO, Medline, Embase, and ISI Web of Science, using the search terms 'social cognition', 'theory of mind', 'emotion recognition', 'attributional style', 'social knowledge', 'social perception', 'empathy', 'at risk mental state', 'clinical high risk', 'psychosis prodrome', and 'ultra high risk'. The pooled effect size (Cohen's D) and the effect sizes for each domain of social cognition were calculated. A random effects model with 95% confidence intervals was used.ResultsSeventeen studies were included in the analysis. The overall significant effect was of medium magnitude (d = 0.52, 95% CI = 0.38-0.65). No moderator effects were found for age, gender and sample size. Sub-analyses demonstrated that individuals in the UHR phase show significant moderate deficits in affect recognition and affect discrimination in faces as well as in voices and in verbal Theory of Mind (TOM). Due to an insufficient amount of studies, we did not calculate an effect size for attributional bias and social perception/knowledge. A majority of studies did not find a correlation between social cognition deficits and transition to psychosis, which may suggest that social cognition in general is not a useful marker for the development of psychosis. However some studies suggest the possible predictive value of verbal TOM and the recognition of specific emotions in faces for the transition into psychosis. More research is needed on these subjects.ConclusionThe published literature indicates consistent general impairments in social cognition in people in the UHR phase, but only very specific impairments seem to predict transition to psychosis.

Importance Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before. Objective To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial. Design Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR. Setting One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment. Intervention After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician. Main outcomes and measures Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters. Results The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates. Conclusions and relevance Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice. Trial registration isrctn.org Identifier: ISRCTN16228411.

This randomized within-subject, double blind study aimed to compare the effects of a single dose of two different antipsychotics (haloperidol and aripiprazole) on cortisol, interleukin (IL)-6 and hippocampal regional Cerebral Blood Flow (rCBF) in the same 17 healthy male individuals. Subjects received a single dose of haloperidol (3 mg), aripiprazole (10 mg) and placebo, in a randomized order on three study appointments.We measured salivary cortisol levels at multiple time points, IL-6 levels from plasma samples, and resting cerebral blood flow (rCBF), using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T). We found significantly lower cortisol levels in the haloperidol condition (F(2,32) = 5.78, p = 0.007), than in either placebo (p = 0.013; CI = 0.45, 0.406) or aripiprazole (p = 0.037; CI = −0.520, −0.014). Interleukin-6 levels were also lower following haloperidol (F(2,22) = 4.19, p = 0.048) in comparison with placebo (p = 0.02; CI = 0.14, 1.8), but not with aripiprazole. Finally, we found a greater rCBF in the right (peak voxel: T = 6.47, p b 0.0001) and left (peak voxel T = 5.17, p b 0.01) hippocampus following haloperidol compared with placebo, and at trend level also in the left hippocampus following aripiprazole compared with placebo (T = 4.07, p = 0.057). These differences in hippocampal rCBF after both antipsychotics were no longer evident (haloperidol) or present at trend level (aripiprazole), after controlling for cortisol and IL-6 levels. Our findings suggest that haloperidol can directly regulate the hypothalamic-pituitary-adrenal (HPA) axis and immune system through a pharmacological action via D2 receptor antagonism. Finally, our data suggest that the increased hippocampal rCBF is a manifestation of the reduction in IL-6 and cortisol which follows the administration of haloperidol.

Significance Early traumatic experiences interact with redox regulation and oxidative stress. Blood glutathione peroxidase (GPx) activity, involved in reducing peroxides, may reflect the oxidation status of the organism, thus allowing for the stratification of patients. Traumatized patients with psychosis who have a high blood oxidation status (high-GPx) have smaller hippocampal volumes (but not a smaller amygdala or intracranial volume), and this is associated with more severe clinical symptoms, while those with a lower oxidation status (low-GPx) showed better cognition and a correlated activation of the antioxidant thioredoxin/peroxiredoxin system. Thus, in patients with psychosis, traumatic experiences during childhood may interact with various redox systems, leading to long-term neuroanatomical and clinical defects. This redox profile may represent important biomarkers for patient stratification, defining treatment strategies at early stages of psychosis., Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low-GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis.