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Background and Hypothesis: The negative symptoms of schizophrenia are strong prognostic factors but remain poorly understood and treated. Five negative symptom domains are frequently clustered into the motivation and pleasure (MAP) and emotional expression (EE) 'dimensions', but whether this structure remains stable and behaves as a single entity or not remains unclear., Study Design: We examined a cohort of 153 patients taking clozapine for treatment-resistant schizophrenia in a regional mental health clinic. Patients were assessed longitudinally over a mean period of 45 months using validated scales for positive, negative and mood symptoms. Network analyses were performed to identify symptom 'communities' and their stability over time. The influence of common causes of secondary negative symptoms as well as centrality measures were also examined., Study Results: Across patients at baseline, two distinct communities matching the clinical domains of MAP and EE were found. These communities remained highly stable and independent over time. The communities remained stabled when considering psychosis, depression, and sedation severity, and these causes of secondary negative symptoms were clustered into the MAP community. Centrality measures also remained stable over time, with similar centrality measures across symptoms., Conclusions: Our results suggest that MAP and EE are independent dimensions that remain highly stable over time in chronic schizophrenia patients treated with clozapine. Common causes of secondary negative symptoms mapped onto the MAP dimension. Our results emphasise the need for clinical trials to address either MAP or EE, and that treating causes of secondary negative symptoms may improve MAP., Competing Interests: Declaration of Competing Interest, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Childhood adversity and cannabis use are considered independent risk factors for psychosis, but whether different patterns of cannabis use may be acting as mediator between adversity and psychotic disorders has not yet been explored. The aim of this study is to examine whether cannabis use mediates the relationship between childhood adversity and psychosis., Methods: Data were utilised on 881 first-episode psychosis patients and 1231 controls from the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Detailed history of cannabis use was collected with the Cannabis Experience Questionnaire. The Childhood Experience of Care and Abuse Questionnaire was used to assess exposure to household discord, sexual, physical or emotional abuse and bullying in two periods: early (0-11 years), and late (12-17 years). A path decomposition method was used to analyse whether the association between childhood adversity and psychosis was mediated by (1) lifetime cannabis use, (2) cannabis potency and (3) frequency of use., Results: The association between household discord and psychosis was partially mediated by lifetime use of cannabis (indirect effect coef. 0.078, s.e. 0.022, 17%), its potency (indirect effect coef. 0.059, s.e. 0.018, 14%) and by frequency (indirect effect coef. 0.117, s.e. 0.038, 29%). Similar findings were obtained when analyses were restricted to early exposure to household discord., Conclusions: Harmful patterns of cannabis use mediated the association between specific childhood adversities, like household discord, with later psychosis. Children exposed to particularly challenging environments in their household could benefit from psychosocial interventions aimed at preventing cannabis misuse.

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood., (© 2023. The Author(s).)

Objective: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles., Methods: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups., Results: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset., Conclusions: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paris Alexandros Lalousis has received honoraria for talks presented at educational meetings organised by Boehringer-Ingelheim. Rachel Upthegrove reports grants from Medical Research Council, grants from National Institute for Health Research: Health Technology Assessment, grants from European Commission - Research: The Seventh Framework Programme, and personal speaker fees from Sunovion, outside the submitted work. This study was supported by grant UKRI MR/S037675/1 from the MRC Psychosis Immune Mechanism Stratified Medicine Study (PIMS). It was also supported by the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Christos Pantelis was supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (1105825), an NHMRC L3 Investigator Grant (1196508), and NHMRC-EU grant (1075379); he has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier; and has received honoraria for talks presented at educational meetings organised by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire. Nusrat Husain is a past Trustee of Manchester Global Foundation (MGF), The Pakistan Institute of Living and Learning (PILL), Abaseen Foundation UK and Lancashire Mind UK. He is executive member of the Academic Faculty of the Royal College of Psychiatrists, London. He is a NIHR Senior Investigator. In the last five years he has attended educational events organized by various pharmaceutical industries., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed., (© 2023. Springer Nature Limited.)

Negative symptoms of schizophrenia manifest as reduced motivation and pleasure (MAP) and impaired emotional expressivity (EXP). These can occur as primary phenomena, but have also been suggested to occur secondary to other clinical factors, including antipsychotic-induced sedation. However, this relationship has not been established formally. Here, we examined the effect of antipsychotic-induced sedation (assessed via the proxy of total daily sleep duration) on MAP and EXP in a cohort of 187 clozapine-treated patients with schizophrenia followed for over 2 years on average, using multilevel regression and mediation models. MAP, but not EXP, was adversely influenced by sedation, independently of the severity of psychosis or depression. Moreover, clozapine impaired MAP indirectly by worsening sedation, but after accounting for clozapine-induced sedation, clozapine improved MAP. Our results highlight the importance of addressing sedative side-effects of antipsychotics to improve clinical outcomes.

Background: Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD)., Methods: Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons., Results: In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74)., Conclusions: Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

Background: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation., Method: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF- α ., Results: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ ( F (2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ ( F (2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls., Conclusions: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ&#95;PRS), bipolar disorder (BD&#95;PRS), major depression (MD&#95;PRS), and IQ (IQ&#95;PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean&#95;IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean&#95;IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ&#95;PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ&#95;PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration., Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models., Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007)., Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.

Background and Hypothesis: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition., Study Design: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD)., Study Results: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]., Conclusions: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: It is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies., Methods: Associations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes., Results: The schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses., Conclusions: Our study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

Early psychosis is characterised by heterogeneity in illness trajectories, where outcomes remain poor for many. Understanding psychosis symptoms and their relation to illness outcomes, from a novel network perspective, may help to delineate psychopathology within early psychosis and identify pivotal targets for intervention. Using network modelling in first episode psychosis (FEP), this study aimed to identify: (a) key central and bridge symptoms most influential in symptom networks, and (b) examine the structure and stability of the networks at baseline and 12-month follow-up. Data on 1027 participants with FEP were taken from the National EDEN longitudinal study and used to create regularised partial correlation networks using the 'EBICglasso' algorithm for positive, negative, and depressive symptoms at baseline and at 12-months. Centrality and bridge estimations were computed using a permutation-based network comparison test. Depression featured as a central symptom in both the baseline and 12-month networks. Conceptual disorganisation, stereotyped thinking, along with hallucinations and suspiciousness featured as key bridge symptoms across the networks. The network comparison test revealed that the strength and bridge centralities did not differ significantly between the two networks (C = 0.096153; p = 0.22297). However, the network structure and connectedness differed significantly from baseline to follow-up (M = 0.16405, p = <0.0001; S = 0.74536, p = 0.02), with several associations between psychosis and depressive items differing significantly by 12 months. Depressive symptoms, in addition to symptoms of thought disturbance (e.g. conceptual disorganisation and stereotyped thinking), may be examples of important, under-recognized treatment targets in early psychosis, which may have the potential to lead to global symptom improvements and better recovery., (© 2021. The Author(s).)

Background: Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders., Methods: Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders., Results: Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P < 0.001) than positive symptoms (r pb =0.19; P < 0.001). The associations of CRP with positive and negative symptom dimension scores were similar. At individual symptom level, after adjusting for potential confounders including depressive symptoms, CRP was associated with auditory hallucinations (adjusted OR = 2.22; 95% CI, 1.04-4.76) and anhedonia (adjusted OR = 1.13; 95% CI, 1.02-1.26)., Conclusions: Inflammation is associated with sub-clinical psychotic symptoms in young people in general population. Association of CRP with symptoms commonly shared between mood and psychotic disorders, such as auditory hallucinations and anhedonia, could be one explanation for the apparent trans-diagnostic effect of inflammation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Schizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits with these disorders are likely to be causal, or could be explained by reverse causality/residual confounding., Methods: We used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality, specificity and direction of association of 20 immunological proteins/traits (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory cytokines: IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived neurotrophic factor (BDNF)) with schizophrenia, major depression and bipolar disorder., Results: Genetically-predicted IL-6 was associated with increased risk of schizophrenia in univariable MR (OR = 1.24; 95% C.I., 1.05-1.47) and with major depression in MVMR (OR = 1.08; 95% C.I., 1.03-1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα (OR = 1.07; 95% C.I., 1.01-1.12) and IL-9 (OR = 1.06; 95% C.I., 1.01-1.11) were associated with increased schizophrenia risk. Genetically-predicted BDNF (OR = 0.97; 95% C.I., 0.94-1.00) and MCP-1 (OR = 0.96; 95% C.I., 0.91-0.99) were associated with reduced schizophrenia risk. However, these findings did not survive correction for multiple testing. The CRP-schizophrenia association attenuated completely after taking into account IL-6 and sIL-2Rα in MVMR (OR = 1.02; 95% C.I., 0.81-1.28). No significant associations were observed for bipolar disorder. Evidence from bidirectional MR did not support reverse causality., Conclusions: We report evidence in support of potential causal associations of several immunological proteins/traits with schizophrenia, and of IL-6 with depression. Some of the findings did not survive correction for multiple testing and so replication in larger samples is required. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immunological proteins/pathways for schizophrenia and depression., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03-0.33) and positive (B = 0.19; 95%CI 0.03-0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11-0.52) and in controls (B = 0.26; 95%CI 0.06-0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders., (© 2021. The Author(s).)

Background: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients., Method: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses., Results: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score ( B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use ( B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use., Conclusions: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

Background: Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia., Methods and Findings: We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38-6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36-0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37-2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85-1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant., Conclusions: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., Competing Interests: We have read the journal's policy and the authors of this manuscript have the following competing interests. SB is a paid statistical consultant on PLOS Medicine's statistical board. CL is an Academic Editor on PLOS Medicine's editorial board. PBJ has received honoraria for providing scientific advice to Jansen, Ricordati and Lundbeck.

Background: Individuals diagnosed with schizophrenia are often assigned other psychiatric diagnoses during their lives. The significance of changing diagnosis has not been widely studied., Aims: Our aim was to examine the association between diagnostic change and later outcome., Methods: Individuals' diagnostic history, clinical and social outcomes were extracted from the AESOP-10 study, a 10-year follow-up of first episode psychosis cases. The association between outcome and different patterns of diagnosis over time were assessed using linear or logistic regression., Results: Individuals always diagnosed with schizophrenia ( n  = 136) had worse clinical and social outcomes at follow-up than those never diagnosed with schizophrenia ( n  = 163), being more likely to be symptomatic, unemployed, single, and socially isolated. There was no difference in outcome between individuals always diagnosed with schizophrenia and those changing to a diagnosis of schizophrenia ( n  = 60), and no difference in outcome between individuals never diagnosed with schizophrenia, and those changing from a diagnosis of schizophrenia ( n  = 44)., Conclusions: Individuals always and never diagnosed with schizophrenia had different outcomes. In cases of diagnostic instability participants had similar outcomes to those always assigned the diagnosis they changed to irrespective of initial diagnosis.

Minor neurological signs are subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts present in excess in the early stages of psychosis. Still, it remains unclear whether at least some of these signs represent trait or state markers for psychosis and whether they are markers of long-term disease outcome of clinical utility. We examined the relationship between neurological function at illness onset assessed with the Neurological Evaluation Scale and subsequent illness course in 233 patients from AESOP-10 (Aetiology and Ethnicity in Schizophrenia and Other Psychoses), a 10-year follow-up study of a population-based cohort of individuals recruited at the time of their first episode of psychosis in the United Kingdom. In 56 of these patients, we also explored changes in neurological function over time. We included a group of 172 individuals without psychosis as controls. After 10 years, 147 (63%) patients had developed a non-remitting course of illness, and 86 (37%) a remitting course. Already at first presentation, patients who developed a non-remitting course had significantly more primary, motor coordination, and total signs than both remitting patients and healthy controls. While Motor Coordination signs did not change over time, rates of Primary, Sensory Integration, and Total signs increased, independently of illness course type. These findings suggest that motor coordination problems could be a useful early, quick, and easily detectable marker of subsequent clinical outcome. With other motor abnormalities, a measure of motor incoordination could contribute to the identification of the most vulnerable individuals, who could benefit from targeted and more assertive treatment approaches., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Immune dysfunction has been implicated in negative symptoms of schizophrenia and also in depression. These disorders are frequently co-morbid, with some symptoms such as anhedonia and apathy common to both. The anti-inflammatory agent minocycline may be ineffective in schizophrenia, but more positive effects have been seen in depression. Our aim was to investigate the role of immune dysfunction in depression and sub-domains of negative symptoms in schizophrenia by investigating their intercorrelation and the influence of treatment with minocycline., Methods: We analysed longitudinal data from 207 patients within 5 years of onset of schizophrenia, from the randomised double-blind, placebo-controlled trial of minocycline (BeneMin). Symptom ratings and circulating IL-6, C-reactive protein (CRP) and TNF-α concentrations were collected at baseline and repeated over twelve months. The sample was not stratified by CRP prior to randomisation. Positive and Negative Syndrome Scale composite ratings of avolition-apathy and diminished expression, Calgary Depression Scale total scores, and immune markers were examined cross-sectionally using Spearman's rank, and longitudinally by linear mixed effect models that included body mass index and minocycline. Additionally, post hoc analysis of the sample stratified by elevated CRP (>1 mg/l and <10 mg/l at baseline) was carried out to assess whether minocycline had any effect on specific symptoms in an immune active sub-group of patients., Results: Depression and avolition-apathy were significantly positively related, and depression correlated weakly with IL-6 at baseline. Diminished expression was associated with increased TNF-α both cross-sectionally and longitudinally. CRP was unrelated to any symptom domain. Minocycline did not affect any individual symptom or sub-domain in the full sample or in the immune active sub-group., Discussion: IL-6 may have some specificity to depression in early schizophrenia. TNF-α may be an indicator of immune dysfunction relevant to negative symptoms, and our longitudinal findings add to this evidence. However, minocycline continues to show very little promise as a treatment for any symptom dimension of early schizophrenia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation., Methods: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses., Results: Genetic predisposition for T2DM was associated with PEs (adjusted OR = 1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR = 1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR = 1.10; 95% C·I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p = .040)., Conclusions: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Schizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning., Methods: We administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n = 29, F|M = 0.81), At Risk Mental State for psychosis (ARMS, n = 23, F|M = 0.35) and FEP (First-episode psychosis, n = 26, F|M = 0.18). Study 2 included healthy adolescents (n = 735, F|M = 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated., Results: Patients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology., Conclusions: Reinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Genetic risk is thought to drive clinical variation on a spectrum of schizophrenia-like traits, but the underlying changes in brain structure that mechanistically link genomic variation to schizotypal experience and behavior are unclear., Methods: We assessed schizotypy using a self-reported questionnaire and measured magnetization transfer as a putative microstructural magnetic resonance imaging marker of intracortical myelination in 68 brain regions in 248 healthy young people (14-25 years of age). We used normative adult brain gene expression data and partial least squares analysis to find the weighted gene expression pattern that was most colocated with the cortical map of schizotypy-related magnetization., Results: Magnetization was significantly correlated with schizotypy in the bilateral posterior cingulate cortex and precuneus (and for disorganized schizotypy, also in medial prefrontal cortex; all false discovery rate-corrected ps < .05), which are regions of the default mode network specialized for social and memory functions. The genes most positively weighted on the whole-genome expression map colocated with schizotypy-related magnetization were enriched for genes that were significantly downregulated in two prior case-control histological studies of brain gene expression in schizophrenia. Conversely, the most negatively weighted genes were enriched for genes that were transcriptionally upregulated in schizophrenia. Positively weighted (downregulated) genes were enriched for neuronal, specifically interneuronal, affiliations and coded a network of proteins comprising a few highly interactive "hubs" such as parvalbumin and calmodulin., Conclusions: Microstructural magnetic resonance imaging maps of intracortical magnetization can be linked to both the behavioral traits of schizotypy and prior histological data on dysregulated gene expression in schizophrenia., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: To determine the baseline individual characteristics that predicted symptom recovery and functional recovery at 10-years following the first episode of psychosis., Methods: AESOP-10 is a 10-year follow up of an epidemiological, naturalistic population-based cohort of individuals recruited at the time of their first episode of psychosis in two areas in the UK (South East London and Nottingham). Detailed information on demographic, clinical, and social factors was examined to identify which factors predicted symptom and functional remission and recovery over 10-year follow-up. The study included 557 individuals with a first episode psychosis. The main study outcomes were symptom recovery and functional recovery at 10-year follow-up., Results: At 10 years, 46.2% (n = 140 of 303) of patients achieved symptom recovery and 40.9% (n = 117) achieved functional recovery. The strongest predictor of symptom recovery at 10 years was symptom remission at 12 weeks (adj OR 4.47; CI 2.60-7.67); followed by a diagnosis of depression with psychotic symptoms (adj OR 2.68; CI 1.02-7.05). Symptom remission at 12 weeks was also a strong predictor of functional recovery at 10 years (adj OR 2.75; CI 1.23-6.11), together with being from Nottingham study centre (adj OR 3.23; CI 1.25-8.30) and having a diagnosis of mania (adj OR 8.17; CI 1.61-41.42)., Conclusions: Symptom remission at 12 weeks is an important predictor of both symptom and functional recovery at 10 years, with implications for illness management. The concepts of clinical and functional recovery overlap but should be considered separately.

Purpose: The EUropean Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study contains an unparalleled wealth of comprehensive data that allows for testing hypotheses about (1) variations in incidence within and between countries, including by urbanicity and minority ethnic groups; and (2) the role of multiple environmental and genetic risk factors, and their interactions, in the development of psychotic disorders., Methods: Between 2010 and 2015, we identified 2774 incident cases of psychotic disorders during 12.9 million person-years at risk, across 17 sites in 6 countries (UK, The Netherlands, France, Spain, Italy, and Brazil). Of the 2774 incident cases, 1130 cases were assessed in detail and form the case sample for case-control analyses. Across all sites, 1497 controls were recruited and assessed. We collected data on an extensive range of exposures and outcomes, including demographic, clinical (e.g. premorbid adjustment), social (e.g. childhood and adult adversity, cannabis use, migration, discrimination), cognitive (e.g. IQ, facial affect processing, attributional biases), and biological (DNA via blood sample/cheek swab). We describe the methodology of the study and some descriptive results, including representativeness of the cohort., Conclusions: This resource constitutes the largest and most extensive incidence and case-control study of psychosis ever conducted.

Psychotic patients with a lifetime history of cannabis use generally show better cognitive functioning than other psychotic patients. Some authors suggest that cannabis-using patients may have been less cognitively impaired and less socially withdrawn in their premorbid life. Using a dataset comprising 948 patients with first-episode psychosis (FEP) and 1313 population controls across 6 countries, we examined the extent to which IQ and both early academic (Academic Factor [AF]) and social adjustment (Social Factor [SF]) are related to the lifetime frequency of cannabis use in both patients and controls. We expected a higher IQ and a better premorbid social adjustment in psychotic patients who had ever used cannabis compared to patients without any history of use. We did not expect such differences in controls. In both patients and controls, IQ was 3 points higher among occasional-users than in never-users (mean difference [Mdiff] = 2.9, 95% CI = [1.2, 4.7]). Both cases and control daily-users had lower AF compared to occasional (Mdiff = -0.3, 95% CI = [-0.5; -0.2]) and never-users (Mdiff = -0.4, 95% CI = [-0.6; -0.2]). Finally, patient occasional (Mdiff = 0.3, 95% CI = [0.1; 0.5]) and daily-users (Mdiff = 0.4, 95% CI = [0.2; 0.6]) had better SF than their never-using counterparts. This difference was not present in controls (Fgroup*frequency(2, 2205) = 4.995, P = .007). Our findings suggest that the better premorbid social functioning of FEP with a history of cannabis use may have contributed to their likelihood to begin using cannabis, exposing them to its reported risk-increasing effects for Psychotic Disorders., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To estimate the potential gain in life expectancy from addressing modifiable risk factors for all-cause mortality (excluding suicide and deaths from accidents or violence) across specific serious mental illness (SMI) subgroups, namely schizophrenia, schizoaffective disorders, and bipolar disorders in a Western population., Methods: We have used relative risks from recent meta-analyses to estimate the population attribution fraction (PAF) due to specific modifiable risk factors known to be associated with all-cause mortality within SMI. The potential gain in life expectancy at birth, age 50 and age 65 years were assessed by estimating the combined effect of modifiable risk factors from different contextual levels (behavioural, healthcare, social) and accounting for the effectiveness of existing interventions tackling these factors. Projections for annual gain in life expectancy at birth during a two-decade was estimated using the Annual Percentage Change (APC) formula. The predicted estimates were based on mortality rates for year 2014-2015., Results: Based on the effectiveness of existing interventions targeting these modifiable risk factors, we estimated potential gain in life expectancy at birth of four (bipolar disorders), six (schizoaffective disorders), or seven years (schizophrenia). The gain in life expectancy at age 50 years was three (bipolar disorders) or five (schizophrenia and schizoaffective disorders) years. The projected gain in life expectancy at age 65 years was three (bipolar disorders) or four (schizophrenia and schizoaffective disorders) years., Conclusions: The implementation of existing interventions targeting modifiable risk factors could narrow the current mortality gap between the general and the SMI populations by 24% (men) to 28% (women). These projections represent ideal circumstances and without the limitation of overestimation which often comes with PAFs., Competing Interests: Matthew Hotopf is principal investigator of the RADAR-CNS programme, a precompetitive public private partnership funded by the Innovative Medicines Initiative and European Federation of Pharmaceutical Industries and Associations (EFPIA). The programme receives support from Janssen, Biogen, MSD, UCB and Lundbeck. In the last 3 years, Fiona Gaughran has received support or honoraria from Lundbeck, Hikma, Otsuka and Sunovion, and has a family member who has professional links to Lilly and GSK, including shares.

Objective: Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functioning following the first episode with good methodology are rare. The authors examined whether schizophrenia patients experience cognitive decline after the first episode, whether this decline is generalized or confined to individual neuropsychological functions, and whether decline is specific to schizophrenia., Methods: Participants were from a population-based case-control study of patients with first-episode psychosis who were followed prospectively up to 10 years after first admission. A neuropsychological battery was administered at index presentation and at follow-up to patients with a diagnosis of schizophrenia (N=65) or other psychoses (N=41) as well as to healthy comparison subjects (N=103)., Results: The schizophrenia group exhibited declines in IQ and in measures of verbal knowledge and of memory, but not processing speed or executive functions. Processing speed and executive function impairments were already present at the first episode and remained stable thereafter. The magnitude of declines ranged between 0.28 and 0.66 standard deviations. Decline in measures of memory was not specific to schizophrenia and was also apparent in the group of patients with other psychoses. Healthy individuals with low IQ showed no evidence of decline, suggesting that a decline is specific to psychosis., Conclusions: Patients with schizophrenia and other psychoses experience cognitive decline after illness onset, but the magnitude of decline varies across cognitive functions. Distinct mechanisms consequent to the illness and/or psychosocial factors may underlie impairments across different cognitive functions.

Background: Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis., Methods: We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up., Results: Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05)., Conclusions: Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Development of schizophrenia relates to both genetic and environmental factors. Functional deficits in many cognitive domains, including the ability to communicate in social interactions and impaired recognition of facial expressions, are common for patients with schizophrenia and might also be present in individuals at risk of developing schizophrenia. Here we explore whether an individual's polygenic risk score (PRS) for schizophrenia is associated with the degree of interregional similarities in blood oxygen level-dependent (BOLD) signal and gray matter volume of the face-processing network and whether the exposure to early adversity moderates this association. A total of 90 individuals (mean age 22 years, both functional and structural data available) were used for discovery analyses, and 211 individuals (mean age 26 years, structural data available) were used for replication of the structural findings. Both samples were drawn from the Northern Finland Birth Cohort 1986. We found that the degree of interregional similarities in BOLD signal and gray matter volume vary as a function of PRS; lowest interregional correlation (both measures) was observed in individuals with high PRS. We also replicated the gray matter volume finding. We did not find evidence for an interaction between early adversity and PRS on the interregional correlation of BOLD signal and gray matter volume. We speculate that the observed group differences in PRS-related correlations in both modalities may result from differences in the concurrent functional engagement of the face-processing regions over time, eg, via differences in exposure to social interaction with other people., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment., Method: This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions., Results: A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions., Conclusions: Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.

We investigated relationships between early developmental milestones, schizophrenia incidence and variability in its age at onset. We hypothesized that the period of risk for schizophrenia would be longer for those with later development. The Northern Finland Birth Cohort 1966 was followed until 47 years of age, and those members diagnosed with schizophrenia or any other non-affective psychoses identified. Latent profile analysis was used to classify people into homogenous classes with respect to developmental milestones, and subsequently survival analysis explored relationship between classes and age of schizophrenia onset. Results suggest that 4-classes (early, regular, late, and extra late developers) can be identified, but due to few cases in one class (n = 93, <0.01% of 10,501), only 3 classes (early, regular, late) could be meaningfully compared. Schizophrenia incidence until 47 years of age differed systematically between classes: late developers had the highest cumulative incidence (2.39%); regular were intermediate (1.25%); and early developers had the lowest incidence (0.99%). However, age at onset and its variability was similar across classes, suggesting that our hypothesis of a wider 'window' for schizophrenia onset in late developers was not supported., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Previous evidence suggests that delusional disorder has a later onset and better functional outcomes compared to schizophrenia. However, studies have not examined longitudinal outcomes in a first episode population, where confounding factors may be adjusted for., Methods: A nested case control study was designed within the National EDEN study; a cohort of 1027 first episode psychosis patients. Patients with a baseline diagnosis of delusional disorder (n = 48) were compared with schizophrenia (n = 262) at 6 and 12 months with respect to symptomatic and functional outcomes. Regression analysis was used to adjust for possible confounders., Results: Delusional disorder patients had a shorter duration of untreated psychosis compared to schizophrenia but were similar in other baseline characteristics. At baseline, delusional disorder patients had lower symptom scores but higher function scores compared to those with schizophrenia. At 12 months the differences persisted for symptoms scores but not overall function scores. After adjusting for baseline score, age and duration of untreated psychosis, differences between the groups remained significant only for Positive and Negative Syndrome Scale (PANNS) negative, general and total scores and recovery rates. There were no differences in changes in outcomes scores., Conclusions: Delusional disorder in a first episode psychosis population presents with less severe symptoms, higher recovery rates and better functioning than schizophrenia, but at 12 months differences are ameliorated when adjusting for baseline differences., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in the pathogenesis of psychosis., Methods: Population-based data on ESR and IQ from 638 213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. The co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk., Results: Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ = 0.961; 95% confidence interval (CI) 0.960-0.963) and ONAP (adjusted HR = 0.973; 95% CI 0.971-0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR = 1.14; 95% CI 1.01-1.28) and decreased risk for ONAP (adjusted HR = 0.85; 95% CI 0.74-0.96), although these effects were specific to one ESR band (7-10 mm/hr). Familial confounding explained ESR-IQ but not ESR-psychoses associations. IQ partly mediated the ESR-psychosis relationships., Conclusions: Lower IQ is associated with low-grade systemic inflammation and with an increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis.

Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology. We examine how genetic risk for schizophrenia relates to adolescent psychosis-related and internalizing psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of the developmental pathways at this age. PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine the relationships of these PRSs with psychopathology factors modelled within (i) a correlated factors structure and (ii) a bifactor structure. The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression and anxiety, but, when modelling a general psychopathology factor based on these measures, specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology. Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples.

Background: The long-term consequences of discontinuing antipsychotic medication after successful treatment of first-episode psychosis are not well studied. We assess the relation between early maintenance therapy decisions in first-episode psychosis and the subsequent clinical outcome at 10 years., Methods: This is a 10 year follow-up study, spanning Sept 5, 2003, to Dec 30, 2014, of a randomised, double-blind trial in seven centres in Hong Kong in which 178 patients with first-episode psychosis with full positive symptom resolution after at least 1 year of antipsychotic treatment were given maintenance treatment (n=89; oral quetiapine 400 mg daily) or early treatment discontinuation (n=89; placebo) for 12 months. After the trial, patients received naturalistic treatment. Overall this cohort of patients will have received about 3 years of treatment before entering the follow-up phase of the study: about 2 years of maintenance treatment before study entry and 1 year of treatment in the trial. The primary outcome of this follow-up was the proportion of patients in each group (including those for whom direct follow-up was not available) with good or poor long-term clinical outcomes at 10 years, with poor outcome defined as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. The randomised trial was registered with ClinicalTrials.gov, number NCT00334035, and the follow-up study was registered with ClinicalTrials.gov, number NCT01926340., Findings: Poor 10 year clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and 19 (21%) of 89 patients in the maintenance treatment group (risk ratio 1·84, 95% CI 1·15-2·96; p=0·012). Suicide was the only serious adverse event that occurred in the follow-up phase (four [4%] patients in the early discontinuation group vs two [2%] in the maintenance group)., Interpretation: In patients with first-episode psychosis with a full initial response to treatment, medication continuation for at least the first 3 years after starting treatment decreases the risk of relapse and poor long-term clinical outcome., Funding: Food and Health Bureau, Research Grants Council of Hong Kong, and AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Several ethnic minority groups experience elevated rates of first-episode psychosis (FEP), but most studies have been conducted in urban settings. We investigated whether incidence varied by ethnicity, generation status, and age-at-immigration in a diverse, mixed rural, and urban setting., Method: We identified 687 people, 16-35 years, with an ICD-10 diagnosis of FEP, presenting to Early Intervention Psychosis services in the East of England over 2 million person-years. We used multilevel Poisson regression to examine incidence variation by ethnicity, rural-urban setting, generation status, and age-at-immigration, adjusting for several confounders including age, sex, socioeconomic status, population density, and deprivation., Results: People of black African (incidence rate ratio: 4.06; 95% confidence interval [CI]: 2.63-6.25), black Caribbean (4.63; 95% CI: 2.38-8.98) and Pakistani (2.31; 95% CI: 1.35-3.94) origins were at greatest FEP risk relative to the white British population, after multivariable adjustment. Non-British white migrants were not at increased FEP risk (1.00; 95% CI: 0.77-1.32). These patterns were independently present in rural and urban settings. For first-generation migrants, migration during childhood conferred greatest risk of psychotic disorders (2.20; 95% CI: 1.33-3.62)., Conclusions: Elevated psychosis risk in several visible minority groups could not be explained by differences in postmigratory socioeconomic disadvantage. These patterns were observed across rural and urban areas of our catchment, suggesting that elevated psychosis risk for some ethnic minority groups is not a result of selection processes influencing rural-urban living. Timing of exposure to migration during childhood, an important social and neurodevelopmental window, may also elevate risk., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background There is limited information on the presentation and characteristics of psychotic illness experienced by people with autism spectrum disorder (ASD). Aims To describe autistic and psychotic phenomenology in a group of individuals with comorbid ASD and psychosis (ASD-P) and compare this group with populations affected by either, alone. Method We studied 116 individuals with ASD-P. We compared features of their ASD with people with ASD and no comorbid psychosis (ASD-NP), and clinical characteristics of psychosis in ASD-P with people with psychosis only. Results Individuals with ASD-P had more diagnoses of atypical psychosis and fewer of schizophrenia compared with individuals with psychosis only. People with ASD-P had fewer stereotyped interests/behaviours compared with those with ASD-NP. Conclusions Our data show there may be a specific subtype of ASD linked to comorbid psychosis. The results support findings that psychosis in people with ASD is often atypical, particularly regarding affective disturbance., (© The Royal College of Psychiatrists 2017.)

This naturalistic study analysed the association between cumulative lifetime antipsychotic dose and cognition in schizophrenia after an average of 16.5 years of illness. Sixty participants with schizophrenia and 191 controls from the Northern Finland Birth Cohort 1966 were assessed at age 43 years with a neurocognitive test battery. Cumulative lifetime antipsychotic dose-years were collected from medical records and interviews. The association between antipsychotic dose-years and a cognitive composite score based on principal component analysis was analysed using linear regression. Higher lifetime antipsychotic dose-years were significantly associated with poorer cognitive composite score, when adjusted for gender, onset age and lifetime hospital treatment days. The effects of typical and atypical antipsychotics did not differ. This is the first report of an association between cumulative lifetime antipsychotic dose and global cognition in midlife schizophrenia. Based on these data, higher lifetime antipsychotic dose-years may be associated with poorer cognitive performance at age 43 years. Potential biases related to the naturalistic design may partly explain the results; nonetheless, it is possible that large antipsychotic doses harm cognition in schizophrenia in the long-term., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Meta-analyses of cross-sectional studies confirm an increase in circulating inflammatory markers during acute psychosis. Longitudinal studies are scarce but are needed to understand whether elevated inflammatory markers are a cause or consequence of illness. We report a longitudinal study of serum C-reactive protein (CRP) in adolescence and subsequent risk of schizophrenia and related psychoses in adulthood in the Northern Finland Birth Cohort 1986., Method: Serum high-sensitivity CRP was measured at age 15/16 years in 6362 participants. ICD-10 diagnoses of schizophrenia and related psychoses were obtained from centralised hospital inpatient and outpatient registers up to age 27 years. Logistic regression calculated odds ratios (ORs) for psychotic outcomes associated with baseline CRP levels analysed as both continuous and categorical variables using American Heart Association criteria. Age, sex, body mass index, maternal education, smoking, and alcohol use were included as potential confounders., Results: By age 27years, 88 cases of non-affective psychosis (1.38%), of which 22 were schizophrenia (0.35%), were identified. Adolescent CRP was associated with subsequent schizophrenia. The adjusted OR for schizophrenia by age 27yearsfor each standard deviation (SD) increase in CRP levels at age 15/16yearswas 1.25 (95% CI, 1.07-1.46), which was consistent with a linear, dose-response relationship (P-value for quadratic term 0.23). Using CRP as a categorical variable, those with high (>3mg/L) compared with low (<1mg/L) CRP levels at baseline were more likely to develop schizophrenia; adjusted OR 4.25 (95% CI, 1.30-13.93). There was some indication that higher CRP was associated with earlier onset of schizophrenia (r s =-0.40; P=0.07)., Conclusions: A longitudinal association between adolescent CRP levels and adult schizophrenia diagnosis indicates a potentially important role of inflammation in the pathogenesis of the illness, although the findings, based on a small number of cases, need to be interpreted with caution and require replication in other samples., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophreniaen massecontribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n= 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n= 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P= .001) and lower full IQ (P= .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P= 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (rG= -.379,P= 6.62E-05) and full IQ (rG= -.202,P= 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Importance: Schizophrenia is a highly heritable, polygenic condition characterized by a relatively diverse phenotype and frequent comorbid conditions, such as anxiety and depression. At present, limited evidence explains how genetic risk for schizophrenia is manifest in the general population., Objective: To investigate the extent to which genetic risk for schizophrenia is associated with different phenotypes during adolescence in a population-based birth cohort., Design, Setting, and Participants: This cohort study used data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Of 14,062 children in the birth cohort, genetic data were available for 9912 adolescents. Data were collected periodically from September 6, 1990, and collection is ongoing. Data were analyzed from March 4 to August 13, 2015., Exposures: Polygenic risk scores (PRSs) for schizophrenia generated for individuals in the ALSPAC cohort using results of the second Psychiatric Genomics Consortium Schizophrenia genome-wide association study as a training set., Main Outcomes and Measures: Logistic regression was used to assess associations between the schizophrenia PRS and (1) psychotic experiences (Psychosis-Like Symptom Interview at 12 and 18 years of age), (2) negative symptoms (Community Assessment of Psychic Experiences at 16.5 years of age), (3) depressive disorder (Development and Well-Being Assessment at 15.5 years of age), and (4) anxiety disorder (Development and Well-Being Assessment at 15.5 years of age) in adolescence., Results: Of the 8230 ALSPAC participants whose genetic data passed quality control checks (51.2% male, 48.8% female), 3676 to 5444 participated in assessments from 12 to 18 years of age. The PRSs created using single-nucleotide polymorphisms with a training-set P ≤ .05 threshold were associated with negative symptoms (odds ratio [OR] per SD increase in PRS, 1.21; 95% CI, 1.08-1.36; R(2) = 0.007) and anxiety disorder (OR per SD increase in PRS, 1.17; 95% CI, 1.06- 1.29; R(2) = 0.005). No evidence was found of an association between schizophrenia PRS and psychotic experiences (OR per SD increase in PRS, 1.08; 95% CI, 0.98-1.19; R(2) = 0.001) or depressive disorder (OR per SD increase in PRS, 1.02; 95% CI, 0.91-1.13; R(2) = 0.00005). Results were mostly consistent across different training-set P value thresholds and using different cutoffs and measures of the psychopathological outcomes., Conclusions and Relevance: This study demonstrates polygenic overlaps between common genetic polymorphisms associated with schizophrenia and negative symptoms and anxiety disorder but not with psychotic experiences or depression. Because the genetic risk for schizophrenia appears to be manifest as anxiety and negative symptoms during adolescence, a greater focus on these phenotypes rather than on psychotic experiences might be required for prediction of transition in at-risk samples., Competing Interests: Disclosures: Dr O'Donovan received a consultancy fee from Roche in July 2015. No other disclosures were reported.

Background: Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators., Method: Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age=34.7, SD=0.77) and at follow-up (mean age=43.4, SD=0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA., Results: Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction., Conclusion: Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions., (Copyright © 2015. Published by Elsevier B.V.)