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About one in 100 people worldwide are diagnosed with schizophrenia. Many people advocate for a name change for the condition, pointing to the stigma and discrimination associated with the term "schizophrenia", as well as to how the name poorly characterizes features of the illness. The purpose of this project was to collect opinions from a broad, diverse sample of stakeholders about possible name changes for schizophrenia. The project represented a partnership between researchers, clinicians, and those with lived experience with psychosis. The group developed a survey to assess opinions about the need for change in the name schizophrenia as well as potential alternate names. We accumulated 1190 responses from a broad array of community stakeholders, including those with lived experience of mental illness, family members, clinicians, researchers, government officials, and the general public. Findings indicated that the majority of respondents (74.1%) favored a name change for schizophrenia. Most (71.4%) found the name stigmatizing. Of the proposed alternate names, those with the most support included "Altered Perception Syndrome", "Psychosis Spectrum Syndrome", and "Neuro-Emotional Integration Disorder". Survey findings provide strong support for renaming schizophrenia. Most expressed hope that a name change will reduce stigma and discrimination., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FA T ) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FA T in adolescence, and 4% lower FA T by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA T or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

We aimed to systematically synthesize and quantify the utility of pre-treatment resting-state functional magnetic resonance imaging (rs-fMRI) in predicting antipsychotic response in schizophrenia. We searched the PubMed/MEDLINE database for studies that examined the magnitude of association between baseline rs-fMRI assessment and subsequent response to antipsychotic treatment in persons with schizophrenia. We also performed meta-analyses for quantifying the magnitude and accuracy of predicting response defined continuously and categorically. Data from 22 datasets examining 1280 individuals identified striatal and default mode network functional segregation and integration metrics as consistent determinants of treatment response. The pooled correlation coefficient for predicting improvement in total symptoms measured continuously was ~0.47 (12 datasets; 95% CI: 0.35 to 0.59). The pooled odds ratio of predicting categorically defined treatment response was 12.66 (nine datasets; 95% CI: 7.91-20.29), with 81% sensitivity and 76% specificity. rs-fMRI holds promise as a predictive biomarker of antipsychotic treatment response in schizophrenia. Future efforts need to focus on refining feature characterization to improve prediction accuracy, validate prediction models, and evaluate their implementation in clinical practice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group-level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject-level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject-level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free-water) dMRI measures, were calculated by means of age and sex-adjusted z-scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z-scores than are found with raw values (p < .001), predictions based on summary z-score measures achieved low predictive power (AUC < 0.63). Instead, we find that combining information from the different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance (the best predictor achieved AUC = 0.726). Our findings suggest that extreme deviations from a normative model are not optimal features for prediction. However, including the complete distribution of deviations across multiple imaging measures improves prediction, and could aid in subject-level classification., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features., Methods: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2)., Results: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups., Conclusions: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Impaired emotional processing and cognitive functioning are common in schizophrenia, schizoaffective disorder, and bipolar disorders, causing significant socioemotional disability. While a large body of research demonstrates abnormal cognition/emotion interactions in these disorders, previous studies investigating abnormalities in the emotional scene response using event-related potentials (ERPs) have yielded mixed findings, and few studies compare findings across psychiatric diagnoses. The current study investigates the effects of emotion and repetition on ERPs in a large, well-characterized sample of participants with schizophrenia-bipolar syndromes. Two ERP components that are modulated by emotional content and scene repetition, the early posterior negativity (EPN) and late positive potential (LPP), were recorded in healthy controls and participants with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, and bipolar disorder without psychosis. Effects of emotion and repetition were compared across groups. Results displayed significant but small effects in schizophrenia and schizoaffective disorder, with diminished EPN amplitudes to neutral and novel scenes, reduced LPP amplitudes to emotional scenes, and attenuated effects of scene repetition. Despite significant findings, small effect sizes indicate that emotional scene processing is predominantly intact in these disorders. Multivariate analyses indicate that these mild ERP abnormalities are related to cognition, psychosocial functioning, and psychosis severity. This relationship suggests that impaired cognition, rather than diagnosis or mood disturbance, may underlie disrupted neural scene processing in schizophrenia-bipolar syndromes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia., Methods: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis., Results: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated., Conclusions: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Investigating biomarkers in unaffected relatives (UR) of individuals with psychotic disorders has already proven productive in research on psychosis neurobiology. However, there is considerable heterogeneity among UR based on features linked to psychosis vulnerability. Here, using the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) dataset, we examined cognitive and neurophysiologic biomarkers in first-degree UR of psychosis probands, stratified by 2 widely used risk factors: familiality status of the respective proband (the presence or absence of a first- or second-degree relative with a history of psychotic disorder) and age (within or older than the common age range for developing psychosis). We investigated biomarkers that best differentiate the above specific risk subgroups. Additionally, we examined the relationship of biomarkers with Polygenic Risk Scores for Schizophrenia (PRSSCZ) in a subsample of Caucasian probands and healthy controls (HC). Our results demonstrate that the Brief Assessment of Cognition in Schizophrenia (BACS) score, antisaccade error (ASE) factor, and stop-signal task (SST) factor best differentiate UR (n = 169) from HC (n = 137) (P = .013). Biomarker profiles of UR of familial (n = 82) and non-familial (n = 83) probands were not significantly different. Furthermore, ASE and SST factors best differentiated younger UR (age ≤ 30) (n = 59) from older UR (n = 110) and HC from both age groups (age ≤ 30 years, n=49; age > 30 years, n = 88) (P < .001). In addition, BACS (r = -0.175, P = .006) and ASE factor (r = 0.188, P = .006) showed associations with PRSSCZ. Taken together, our findings indicate that cognitive biomarkers-"top-down inhibition" impairments in particular-may be of critical importance as indicators of psychosis vulnerability., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

An important issue affecting genome-wide association studies with deep phenotyping (multiple correlated phenotypes) is determining the suitable family-wise significance threshold. Straightforward family-wise correction (Bonferroni) of p < 0.05 for 4.3 million genotypes and 335 phenotypes would give a threshold of p < 3.46E-11. This would be too conservative because it assumes all tests are independent. The effective number of tests, both phenotypic and genotypic, must be adjusted for the correlations between them. Spectral decomposition of the phenotype matrix and LD-based correction of the number of tested SNPs are currently used to determine an effective number of tests. In this paper, we compare these calculated estimates with permutation-determined family-wise significance thresholds. Permutations are performed by shuffling individual IDs of the genotype vector for this dataset, to preserve correlation of phenotypes. Our results demonstrate that the permutation threshold is influenced by minor allele frequency (MAF) of the SNPs, and by the number of individuals tested. For the more common SNPs (MAF > 0.1), the permutation family-wise threshold was in close agreement with spectral decomposition methods. However, for less common SNPs (0.05 < MAF ≤ 0.1), the permutation threshold calculated over all SNPs was off by orders of magnitude. This applies to the number of individuals studied (here 777) but not to very much larger numbers. Based on these findings, we propose that the threshold to find a particular level of family-wise significance may need to be established using separate permutations of the actual data for several MAF bins., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

"Resting-state" functional magnetic resonance imaging (rs-fMRI) is widely used to study brain connectivity. So far, researchers have been restricted to measures of functional connectivity that are computationally efficient but undirected, or to effective connectivity estimates that are directed but limited to small networks. Here, we show that a method recently developed for task-fMRI-regression dynamic causal modeling (rDCM)-extends to rs-fMRI and offers both directional estimates and scalability to whole-brain networks. First, simulations demonstrate that rDCM faithfully recovers parameter values over a wide range of signal-to-noise ratios and repetition times. Second, we test construct validity of rDCM in relation to an established model of effective connectivity, spectral DCM. Using rs-fMRI data from nearly 200 healthy participants, rDCM produces biologically plausible results consistent with estimates by spectral DCM. Importantly, rDCM is computationally highly efficient, reconstructing whole-brain networks (>200 areas) within minutes on standard hardware. This opens promising new avenues for connectomics., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Theory of Mind (ToM) refers to the ability to perceive others' mental states. Lower ToM has often been associated with poorer functional outcomes in schizophrenia, making it an important treatment target. However, little is known about the underlying neural mechanisms associated with ToM impairments in early course schizophrenia. This study aimed to validate the False Belief task to measure ToM in schizophrenia and to identify aberrant brain activity associated with impairments. 36 individuals with early course schizophrenia and 17 controls were administered the Hinting Task and performed a functional magnetic resonance imaging (fMRI) False Belief task. Between-group differences were examined in a priori regions of interest (ROIs) known to be associated with ToM tasks: medial prefrontal cortex, ventral medial prefrontal cortex, and both the left and right temporal parietal junction (TPJ). We observed a significant positive association between Hinting Task performance and False Belief accuracy, validating the False Belief task as a measure of ToM. Compared to controls, individuals with schizophrenia exhibited reduced brain activation in all four ROIs during the fMRI False Belief task. Furthermore, task-related activations in bilateral TPJs were shown to be positively associated with ToM abilities regardless of diagnosis. Individuals with schizophrenia with lower performance on the False Belief task showed significant reductions in task-related activation in the bilateral TPJ compared to controls, while reductions were not significant for those with higher performance. Our findings suggest that lower neural activity in the bilateral TPJ are associated with ToM impairments observed in individuals with early course schizophrenia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Treatment delay and non-adherence in first episode psychosis is a pressing public health problem. Ambivalence regarding psychiatric intervention and labeling among young people with psychosis is a contributing factor. For these individuals, caregivers often facilitate the pathway to care and support ongoing engagement and adherence. Caregivers describe distress and burden associated with this role. This manuscript describes the development and pilot feasibility testing of a motivational interviewing-derived communication training for caregivers of individuals with untreated or under-treated early course psychosis. Individuals with lived experience were consulted in the intervention development process. The training consisted of four 60-min sessions teaching the philosophy and basic skills of motivational interviewing as well as two brief practice calls. Feasibility was assessed with regard to study enrollment, retention, and completion. Satisfaction was assessed through the Client Satisfaction Questionnaire and qualitative feedback. Thirty-one caregivers consented to this pilot feasibility trial and participated via telehealth over the course of 5 months. Intervention completion and reported satisfaction were high, with 94% of consented participants completing at least three training sessions and 84% reporting that they would "definitely" recommend the training to a friend in similar circumstances. There were no between-clinician differences in MILO session attendance ( F [2] = 0.53, p = 0.596) or satisfaction total scores ( F [2] = 1.03, p = 0.371). Brief motivational interviewing skills training appears to be a feasible and valued intervention for caregivers of individuals with poorly managed early course psychosis. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04010747., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kline, Thibeau, Sanders, English, Davis, Fenley and Keshavan.)

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatment with clozapine can improve the functional outcomes of schizophrenia patients. As for the naturalistic follow-up phase, time to all-cause treatment failure, marked by its discontinuation is selected as the primary outcome, since it reflects both efficacy and side effects. The all-cause discontinuation is defined as discontinuing for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. The results of the SMART-CAT trial will provide evidence for the selection of antipsychotics in FES patients who fail to respond to the first trial of an antipsychotic drug. It will also provide evidence for the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs. The study is based on the combination of sequential therapy and dynamic therapy, which can be more suitable to assess the effectiveness of treatment options in the real-world clinical setting. As a result, we hope that this study can provide guidance for an optimal treatment algorithm in first-episode schizophrenia patients. Trial registration: ID NCT03510325 in ClinicalTrials.gov., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Social cognition has not previously been assessed in treatment-naive patients with chronic schizophrenia, in patients over 60 years of age, or in patients with less than 5 years of schooling., Methods: We revised a commonly used measure of social cognition, the Reading the Mind in the Eyes Test (RMET), by expanding the instructions, using both self-completion and interviewer-completion versions (for illiterate respondents), and classifying each test administration as 'successfully completed' or 'incomplete'. The revised instrument (RMET-CV-R) was administered to 233 treatment-naive patients with chronic schizophrenia (UT), 154 treated controls with chronic schizophrenia (TC), and 259 healthy controls (HC) from rural communities in China., Results: In bivariate and multivariate analyses, successful completion rates and RMET-CV-R scores (percent correct judgments about emotion exhibited in 70 presented slides) were highest in HC, intermediate in TC, and lowest in UT (adjusted completion rates, 97.0, 72.4, and 49.9%, respectively; adjusted RMET-CV-R scores, 45.4, 38.5, and 34.6%, respectively; all p < 0.02). Stratified analyses by the method of administration (self-completed v. interviewer-completed) and by education and age ('educated-younger' v. 'undereducated-older') show the same relationship between groups (i.e. NC>TC>UT), though not all differences remain statistically significant., Conclusions: We find poorer social cognition in treatment-naive than in treated patients with chronic schizophrenia. The discriminant validity of RMET-CV-R in undereducated, older patients demonstrates the feasibility of administering revised versions of RMET to patients who may otherwise be considered ineligible due to education or age by changing the method of test administration and carefully assessing respondents' ability to complete the task successfully.

Competing Interests: Declaration of competing interest None.

Background: Only 30% or fewer of individuals at clinical high risk (CHR) convert to full psychosis within 2 years. Efforts are thus underway to refine risk identification strategies to increase their predictive power. Our objective was to develop and validate the predictive accuracy and individualized risk components of a mobile app-based psychosis risk calculator (RC) in a CHR sample from the SHARP (ShangHai At Risk for Psychosis) program., Method: In total, 400 CHR individuals were identified by the Chinese version of the Structured Interview for Prodromal Syndromes. In the first phase of 300 CHR individuals, 196 subjects (65.3%) who completed neurocognitive assessments and had at least a 2-year follow-up assessment were included in the construction of an RC for psychosis. In the second phase of the SHARP sample of 100 subjects, 93 with data integrity were included to validate the performance of the SHARP-RC., Results: The SHARP-RC showed good discrimination of subsequent transition to psychosis with an AUC of 0.78 (p < 0.001). The individualized risk generated by the SHARP-RC provided a solid estimation of conversion in the independent validation sample, with an AUC of 0.80 (p = 0.003). A risk estimate of 20% or higher had excellent sensitivity (84%) and moderate specificity (63%) for the prediction of psychosis. The relative contribution of individual risk components can be simultaneously generated. The mobile app-based SHARP-RC was developed as a convenient tool for individualized psychosis risk appraisal., Conclusions: The SHARP-RC provides a practical tool not only for assessing the probability that an individual at CHR will develop full psychosis, but also personal risk components that might be targeted in early intervention.

The B-SNIP consortium identified three brain-based Biotypes across the psychosis spectrum, independent of clinical phenomenology. To externally validate the Biotype model, we used free-water fractional volume (FW) and free-water corrected fractional anisotropy (FA T ) to compare white matter differences across Biotypes and clinical diagnoses. Diffusion tensor imaging data from 167 individuals were included: 41 healthy controls, 55 schizophrenia probands, 47 schizoaffective disorder probands, and 24 probands with psychotic bipolar disorder. Compared to healthy controls, FAt reductions were observed in the body of corpus callosum (BCC) for schizoaffective disorder (d = 0.91) and schizophrenia (d = 0.64). Grouping by Biotype, Biotype 1 showed FAt reductions in the CC and fornix, with largest effect in the BCC (d = 0.87). Biotype 2 showed significant FAt reductions in the BCC (d = 0.90). Schizoaffective disorder individuals had elevated FW in the CC, fornix and anterior corona radiata (ACR), with largest effect in the BCC (d = 0.79). Biotype 2 showed elevated FW in the CC, fornix and ACR, with largest effect in the BCC (d = 0.94). While significant diagnosis comparisons were observed, overall greater discrimination from healthy controls was observed for lower FAt in Biotype 1 and elevated FW in Biotype 2. However, between-group differences were modest, with one region (cerebral peduncle) showing a between-Biotype effect. No between-group effects were observed for diagnosis groupings., (Copyright © 2020. Published by Elsevier B.V.)

Background: Antipsychotics are widely used for treating patients with psychosis, and target threshold psychotic symptoms. Individuals at clinical high risk (CHR) for psychosis are characterized by subthreshold psychotic symptoms. It is currently unclear who might benefit from antipsychotic treatment. Our objective was to apply a risk calculator (RC) to identify people that would benefit from antipsychotics., Methods: Drawing on 400 CHR individuals recruited between 2011 and 2016, 208 individuals who received antipsychotic treatment were included. Clinical and cognitive variables were entered into an individualized RC for psychosis; personal risk was estimated and 4 risk components (negative symptoms-RC-NS, general function-RC-GF, cognitive performance-RC-CP, and positive symptoms-RC-PS) were constructed. The sample was further stratified according to the risk level. Higher risk was defined based on the estimated risk score (20% or higher)., Results: In total, 208 CHR individuals received daily antipsychotic treatment of an olanzapine-equivalent dose of 8.7 mg with a mean administration duration of 58.4 weeks. Of these, 39 (18.8%) developed psychosis within 2 years. A new index of factors ratio (FR), which was derived from the ratio of RC-PS plus RC-GF to RC-NS plus RC-CP, was generated. In the higher-risk group, as FR increased, the conversion rate decreased. A small group (15%) of CHR individuals at higher-risk and an FR >1 benefitted from the antipsychotic treatment., Conclusions: Through applying a personal risk assessment, the administration of antipsychotics should be limited to CHR individuals with predominantly positive symptoms and related function decline. A strict antipsychotic prescription strategy should be introduced to reduce inappropriate use.

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7-12 years) at familial high risk (FHR) for psychosis ( N = 17), compared to an age and sex-matched group of healthy control (HC) children ( N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC ( p = 0.004) and anterior cerebellum / temporo-occipital cortex ( p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing ( r = 0.60, p = 0.032) and total ( r = 0.69, p = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Collin, Bauer, Anteraper, Gabrieli, Molokotos, Mesholam-Gately, Thermenos, Seidman, Keshavan, Shenton and Whitfield-Gabrieli.)

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10 -7 ) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

Background: EEG responses during auditory paired-stimuli paradigms are putative biomarkers of psychosis syndromes. The initial iteration of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP1) showed unique and common patterns of abnormalities across schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar disorder with psychosis (BDP). This study replicates those findings in new and large samples of psychosis cases and extends them to an important comparison group, bipolar disorder without psychosis (BDNP)., Methods: Paired stimuli responses from 64-sensor EEG recording were compared across psychosis (n = 597; SZ = 225, SAD = 201, BDP = 171), BDNP (n = 66), and healthy (n = 415) subjects from the second iteration of B-SNIP. EEG activity was analyzed in voltage and in the time-frequency domain. Principal component analysis (PCA) over sensors (sPCA) was used to efficiently capture EEG voltage responses to the paired stimuli. Evoked power was calculated via a Morlet wavelet procedure. A frequency PCA divided evoked power data into three frequency bands: Low (4-17 Hz), Beta (18-32 Hz), and Gamma (33-55 Hz). Each time-course (ERP Voltage, Low, Beta, and Gamma) were then segmented into 20 ms bins and analyzed for group differences. To efficiently summarize the multiple EEG components that best captured group differences we used multivariate discriminant and correlational analyses. This approach yields a reduced set of measures that may be useful in subsequent biomarker investigations., Results: Group ANOVAs identified 17 time-ranges that showed significant group differences (p < .05 after FDR correction), constructively replicating B-SNIP1 findings. Multivariate linear discriminant analysis parsimoniously selected variables that best accounted for group differences: The P50 response to S1 and S2 uniquely separated BDNP from healthy and psychosis subjects (BDNP > all other groups); the S1 N100 response separated groups along an axis of psychopathology severity (HC > BDNP > BDP > SAD > SZ); the S1 P200 response indexed psychosis psychopathology (HC/BDNP > SAD/SZ/BDP); and the preparatory period to the S2 stimulus separated SZ from other groups (SZ > SAD/BDP>HC/BDNP).Canonical correlation identified an association between the neural responses during the S1 N100, S1 N200 and S2 preparatory period and PANSS positive symptoms and social functioning. The neural responses during the S1 P50 and S1 N100 were associated with PANSS Negative/General, MADRS and Young Mania symptoms., Conclusions: This study constructively replicated prior B-SNIP1 research on auditory deviations observed during the paired stimuli task in SZ, SAD and BDP. Inclusion of a group of BDNP allows for the identification of biomarkers more closely related to affective versus nonaffective clinical phenotypes and neural distinctions between BDP and BDNP. Findings have implications for nosology and future translational work given that some biomarkers are shared across all psychosis and some are unique to affective syndromes., Competing Interests: Declaration of Competing Interest DA Parker, RL Trotti, JE McDowell, SK Keedy, ES Gershon, EI Ivleva, GD Pearlson, MS Keshavan, CA Tamminga, JA Sweeney, and BA Clementz report no financial interests or potential conflicts of interest related to this project.

Objectives: 1) to assess generalizability of neurocognitive deficits reported in previous Western clinical high-risk (CHR) for psychosis studies in a prodromal program in Shanghai, China; and 2) to investigate neurocognition in CHR subjects in relation to a broader range of clinical outcomes (e.g. remission) than presence or absence of psychosis., Method: Baseline neurocognitive assessments of CHR (n = 217) and healthy control (HC; n = 133) subjects were compared based on 1-year follow-up clinical status using MANOVA. CHR subjects were first divided into 'converter' (CHR-C; n = 41) and 'non-converter' (CHR-NC; n = 155) to psychosis groups and compared to HC and to each other. CHR subjects were then divided into 'remission' (i.e. achieved remission; n = 102), 'symptomatic' (persistent positive symptoms in the absence of conversion; n = 37) and 'poor-outcome' (converted and symptomatic subjects who did not respond to treatment; n = 57) groups., Results: CHR neurocognitive performance was broadly impaired compared to HC; CHR-C subjects showed lower performance in processing speed and visual learning than CHR-NC. CHRs with poor clinical outcomes showed lower performance on most MCCB tasks compared to HC, particularly in learning and processing speed, as clinical outcome worsened from remission to symptomatic to poor outcome groups., Conclusions: Level and pattern of baseline neurocognitive weaknesses in SHARP CHR subjects were similar to those in NAPLS-2. Outcome stratification into remission, symptomatic and poor groups was associated with increasing cognitive deficits in learning and processing speed. These findings support cross-cultural generalizability and advance understanding of CHR neurocognitive heterogeneity associated with 1-year clinical outcomes., Competing Interests: Declaration of competing interest All authors declare that they have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work., (Copyright © 2020. Published by Elsevier B.V.)

Auditory P300 oddball and novel components index working memory operations and salience processing, respectively, and are regarded as biomarkers of neurocognitive changes in both chronic and first-episode schizophrenia. Much less is known about whether P300 abnormalities exist in individuals at clinical high risk for psychosis (CHR) and if they are predictors of both transition to psychosis and remission from symptoms. One hundred and four CHR and 69 healthy control individuals (HC) completed P300 oddball paradigm, and 131 CHR and 69 HC subjects completed P300 novel paradigm. All CHR subjects were followed up for one year and stratified into CHR converters (CHRC) and non-converters (CHR-NC), with CHR-NC further stratified into remitted and non-remitted subgroups. Between-group comparisons of P300 oddball and novel amplitude and latency were performed among CHRC, CHR-NC and HC, as well as among CHRC, non-remitted CHR, remitted CHR and HC. CHR converters had lower fronto-central P300 novel amplitude as well as marginally lower P300 oddball amplitude relative to HC. When CHR non-converters were stratified into remitted and non-remitted subgroups, P300 novel amplitude in remitted CHR subjects was comparable to HC, and it was higher than that in CHR subjects who converted to psychosis or who did not remit. Thus, reduced P300 novel amplitude indexing impaired salience processing marked both conversion to psychosis and remission from psychotic symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Schizophrenia (SZ) is proposed as a disorder of dysconnectivity underlying cognitive impairments and clinical manifestations. Although previous studies have shown extracellular changes in white matter of first-episode SZ, little is known about the transition period towards chronicity and its association with cognition. Free-water (FW) imaging was applied to 79 early course SZ participants and 29 controls to detect white matter axonal and extracellular differences during this phase of illness. Diffusion-weighted images were collected from two sites, harmonized, and processed using a pipeline separately modeling water diffusion in tissue (FAt) and extracellular space (FW). Tract-Based Spatial Statistics was performed using the ENIGMA-DTI protocols. SZ showed FAt reductions in the posterior thalamic radiation (PTR) and FW elevations in the cingulum compared to controls, suggesting FAt and FW changes in the early course of SZ. In SZ, greater FAt of the fornix & stria terminalis (FXST) was positively associated with Theory of Mind performance; average whole-brain FAt, FAt of the FXST and the PTR were positively associated with greater working memory performance; average whole-brain FAt was positively associated with visual learning. Further studies are necessary to better understand the neurobiological mechanisms of SZ for developing intervention strategies to preserve brain structure and function., (Copyright © 2020. Published by Elsevier B.V.)

Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and the nature and degree of social cognitive impairments across psychotic disorders and ASD are similar, suggesting that mechanisms that are known to underpin social impairments in ASD may also play a role in the impairments seen in psychosis. Specifically, in both humans and animal models of ASD, a cerebellar-parietal network has been identified that is directly related to social cognition and social functioning. In this study we examined social cognition and resting-state brain connectivity in people with psychosis and in neurotypical adults. We hypothesized that social cognition would be most strongly associated with cerebellar-parietal connectivity, even when using a whole-brain data driven approach. Methods: We examined associations between brain connectivity and social cognition in a trans-diagnostic sample of people with psychosis ( n = 81) and neurotypical controls ( n = 45). Social cognition was assessed using the social cognition domain score of the MATRICS Consensus Cognitive Battery. We used a multivariate pattern analysis to correlate social cognition with resting-state functional connectivity at the individual voxel level. Results: This approach identified a circuit between right cerebellar Crus I, II and left parietal cortex as the strongest correlate of social cognitive performance. This connectivity-cognition result was observed in both people with psychotic disorders and in neurotypical adults. Conclusions: Using a data-driven whole brain approach we identified a cerebellar-parietal circuit that was robustly associated with social cognitive ability, consistent with findings from people with ASD and animal models. These findings suggest that this circuit may be marker of social cognitive impairment trans-diagnostically and support cerebellar-parietal connectivity as a potential therapeutic target for enhancing social cognition., (Copyright © 2020 Brady, Beermann, Nye, Eack, Mesholam-Gately, Keshavan and Lewandowski.)

Importance: Cognitive deficits constitute core features of schizophrenia, but the trajectories of cognitive difficulties in chronic untreated schizophrenia remain unclear., Objective: To assess the association of neuropsychological deficits with duration of untreated psychosis in individuals with chronic untreated schizophrenia., Design, Setting, and Participants: Community-dwelling individuals with chronic untreated schizophrenia (untreated patient group) and individuals without mental illness (control group) were recruited from predominantly rural communities in Ningxia, China between June 20, 2016, and August 6, 2019, and administered the Structured Clinical Interview for DSM-IV, the Mini-Mental State Examination, an 8-test version of the MATRICS Consensus Cognition Battery adapted for use in individuals with low levels of education, and a measure of social cognition., Main Outcomes and Measures: Comparison of cognitive test scores between the two groups and association of cognitive test scores with duration of untreated schizophrenia., Results: The patient group included 197 individuals with chronic untreated schizophrenia (101 men [51.3%]; mean [SD] age, 52.1 [11.8] years; median [interquartile range] years of schooling, 3 [0-6] years; median [interquartile range] years of untreated psychosis, 22.9 [14.9-32.8] years). The control group included 220 individuals (118 men [53.6%]; mean [SD] age, 52.1 [11.2] years; median [interquartile range] years of schooling, 4 [0-6] years). The untreated patient group performed significantly worse than the control group on all cognitive measures (adjusted partial Spearman correlation coefficient [Spearman ρ] ranged from -0.35 for the revised Chinese version of the Reading the Mind in the Eyes Test to -0.60 for the Brief Visuospatial Memory Test-Revised; P < .001 for all comparisons). Longer durations of untreated psychosis were associated with lower performance in 3 MATRICS Consensus Cognition Battery measures assessing different aspects of executive functioning (Brief Visuospatial Memory Test-Revised [ρ = -0.20; P = .04]; Brief Assessment of Cognition in Schizophrenia, Symbol Coding subtest [ρ = -0.35; P < .001]; and Neuropsychological Assessment Battery, Mazes subtest [ρ = -0.24; P = .01]). The median duration of untreated psychosis (22.9 years) was associated with estimated score reductions in the 3 measures of 34% (95% CI, 10%-52%), 43% (95% CI, 28%-55%), and 57% (95% CI, 31%-73%), respectively., Conclusions and Relevance: The findings of this study suggest that long-term untreated schizophrenia was associated with decreases in selective cognitive abilities; both neurodegenerative pathology and neurodevelopmental dysfunction may be factors in cognition in persistent psychosis. Expanding research to include cohorts of patients from underserved rural communities in low- and middle-income countries may provide new insights about the etiological factors, disease course, and management of schizophrenia.

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

Competing Interests: Declaration of competing interest None.

The treatment of negative symptoms (NS) in psychosis represents an urgent unmet medical need given the significant functional impairment it contributes to psychosis syndromes. The lack of progress in treating NS is impacted by the lack of known pathophysiology or associated quantitative biomarkers, which could provide tools for research. This current analysis investigated potential associations between NS and an extensive battery of behavioral and brain-based biomarkers in 932 psychosis probands from the B-SNIP database. The current analyses examined associations between PANSS-defined NS and (1) cognition, (2) pro-/anti-saccades, (3) evoked and resting-state electroencephalography (EEG), (4) resting-state fMRI, and (5) tractography. Canonical correlation analyses yielded symptom-biomarker constructs separately for each biomarker modality. Biomarker modalities were integrated using canonical discriminant analysis to summarize the symptom-biomarker relationships into a "biomarker signature" for NS. Finally, distinct biomarker profiles for 2 NS domains ("diminished expression" vs "avolition/apathy") were computed using step-wise linear regression. NS were associated with cognitive impairment, diminished EEG response amplitudes, deviant resting-state activity, and oculomotor abnormalities. While a connection between NS and poor cognition has been established, association to neurophysiology is novel, suggesting directions for future mechanistic studies. Each biomarker modality was related to NS in distinct and complex ways, giving NS a rich, interconnected fingerprint and suggesting that any one biomarker modality may not adequately capture the full spectrum of symptomology., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Declaration of competing interest We declare that we have no conflict of interest.

Background: Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum., Methods: We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability., Results: All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability., Conclusions: We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities., Competing Interests: Declaration of competing interest M.Y. Gotra, S.K. Hill, E.S. Gershon, C.A. Tamminga, E.I. Ivleva, G.D. Pearlson, B.A. Clementz, J.E. McDowell, P.F. Buckley, J.A. Sweeney, and S.K. Keedy report no financial interests or potential conflicts. M.S. Keshavan has served as an adviser for Alkermes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype., Competing Interests: Declaration of competing interest Dr. Tamminga is on the board of IntraCellular Technology and an ad hoc consultant for Takeda, Pierre Fabre, and Atiphony. The other authors have no conflicts of interest at this time. The other authors have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features., Methods: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance., Results: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P < .01) and predictive (P = .02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P < .01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P < .001), without a significant difference between the two bipolar patient groups., Conclusions: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed-forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups., (© 2019 The Authors. Bipolar Disorders published by Published by John Wiley & Sons Ltd.)

Subtypes of schizophrenia, constructed using clinical phenomenology to resolve illness heterogeneity, have faced criticism due to overlapping symptomatology and longitudinal instability; they were therefore dropped from the Diagnostic Statistical Manual-5. Cognitive and imaging findings comparing paranoid (P-SZ) and non-paranoid (disorganized, residual and undifferentiated; NP-SZ) schizophrenia have been limited due to small sample sizes. We assessed P-SZ and NP-SZ using symptomatology, cognition and brain structure and predicted that there would be few neurobiological differences. P-SZ (n = 237), NP-SZ (n = 127) and controls (n = 430) were included from a multi-site study. In a subset of this sample, structural imaging measures (P-SZ, n = 133; NP-SZ, n = 67; controls, n = 310) were calculated using Freesurfer 6.0. Group contrasts were run using analysis of covariance, controlling for age, sex, race and site, p-values were corrected using False Discovery Rate (FDR) and were repeated excluding the residual subtype. Compared to NP-SZ (with and without the residual subtype), P-SZ displayed fewer negative symptoms, faster speed of processing, larger bilateral hippocampus, right amygdala and their subfield volumes. Additionally, NP-SZ (with residual subtype) displayed fewer depressive symptoms and higher left transverse temporal cortical thickness (CT) but NP-SZ without residual subtype showed lower GAF scores and worse digit sequencing compared to P-SZ. No differences in positive symptoms and functioning (global or social) were detected. Subtle but significant differences were seen in cognition, symptoms, CT and subcortical volumes between P-SZ and NP-SZ. While the magnitude of these differences is not large enough to justify them as distinct categories, the paranoid- nonparanoid distinction in schizophrenia merits further investigation., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2020. Published by Elsevier B.V.)

Background: Psychiatry aspires to the molecular understanding of its disorders and, with that knowledge, to precision medicine. Research supporting such goals in the dimension of psychosis has been compromised, in part, by using phenomenology alone to estimate disease entities. To this end, we are proponents of a deep phenotyping approach in psychosis, using computational strategies to discover the most informative phenotypic fingerprint as a promising strategy to uncover mechanisms in psychosis., Methods: Doing this, the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has used biomarkers to identify distinct subtypes of psychosis with replicable biomarker characteristics. While we have presented these entities as relevant, their potential utility in clinical practice has not yet been demonstrated., Results: Here we carried out an analysis of clinical features that characterize biotypes. We found that biotypes have unique and defining clinical characteristics that could be used as initial screens in the clinical and research settings. Differences in these clinical features appear to be consistent with biotype biomarker profiles, indicating a link between biological features and clinical presentation. Clinical features associated with biotypes differ from those associated with DSM diagnoses, indicating that biotypes and DSM syndromes are not redundant and are likely to yield different treatment predictions. We highlight 3 predictions based on biotype that are derived from individual biomarker features and cannot be obtained from DSM psychosis syndromes., Conclusions: In the future, biotypes may prove to be useful for targeting distinct molecular, circuit, cognitive, and psychosocial therapies for improved functional outcomes., (Copyright © 2020. Published by Elsevier Inc.)

Background: Autism Spectrum Disorder (ASD) and schizophrenia are neurodevelopmental disorders which share substantial overlap in cognitive deficits during adulthood. However, treatment evaluation in ASD and treatment comparisons across ASD and schizophrenia are limited by a dearth of empirical work establishing the validity of a standard cognitive battery across ASD and schizophrenia. Promisingly, the MATRICS Consensus Cognitive Battery (MCCB) has been validated in schizophrenia and encompasses cognitive domains that are impacted in ASD. Thus, this study aimed to establish MCCB's generalizability from schizophrenia to ASD., Methods: Community-residing adults with schizophrenia (N = 100) and ASD (N = 113) underwent MCCB assessment. Using multigroup confirmatory factor analysis, MCCB's transdiagnostic validity was evaluated by examining whether schizophrenia and ASD demonstrate the same configuration, magnitude, and directionality of relationships within and among measures and their underlying cognitive domains., Results: Across schizophrenia and ASD, the same subsets of MCCB measures inform three cognitive domains: processing speed, attention/working memory, and learning. Except for group means in category fluency, continuous performance, and spatial span, both groups show vastly comparable factor structures and characteristics., Conclusions: To our knowledge, this study is the first to establish the validity of a standard cognitive battery in adults with ASD and furthermore the first to establish a cognitive battery's comparability across ASD and schizophrenia. Cognitive domain scores can be compared across new samples using weighted sums of MCCB scores resulting from this study. These findings highlight MCCB's applicability to ASD and support its utility for standardizing treatment evaluation of cognitive outcomes across the autism-schizophrenia spectrum.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA 1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA 1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, P = 0.578) while fALFF4 decreased (-0.05, -13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times ( P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D., (© 2020 by the American Diabetes Association.)

Recognizing that current frameworks for classification and treatment in psychiatry are inadequate, particularly for use in young people and early intervention services, transdiagnostic clinical staging models have gained prominence. These models aim to identify where individuals lie along a continuum of illness, to improve treatment selection and to better understand patterns of illness continuity, discontinuity and aetiopathogenesis. All of these factors are particularly relevant to help-seeking and mental health needs experienced during the peak age range of onset, namely the adolescent and young adult developmental periods (i.e., ages 12-25 years). To date, progressive stages in transdiagnostic models have typically been defined by traditional symptom sets that distinguish "sub-threshold" from "threshold-level" disorders, even though both require clinical assessment and potential interventions. Here, we argue that staging models must go beyond illness progression to capture additional dimensions of illness extension as evidenced by emergence of mental or physical comorbidity/complexity or a marked change in a linked biological construct. To develop further consensus in this nascent field, we articulate principles and assumptions underpinning transdiagnostic clinical staging in youth mental health, how these models can be operationalized, and the implications of these arguments for research and development of new service systems. We then propose an agenda for the coming decade, including knowledge gaps, the need for multi-stakeholder input, and a collaborative international process for advancing both science and implementation., (© 2020 World Psychiatric Association.)

The current Covid-19 pandemic is posing an unprecedented threat to global well-being and its mental health consequences are just becoming understood. While the crisis has led to a temporary halt in a lot of ongoing or planned psychiatric research, this pandemic is a natural experiment that can help the field to repurpose research to better understand the causes, presentations and outcome trajectories as well as treatments in psychiatry. Inter-disciplinary collaborations between researchers are needed to rapidly develop and share the emerging new knowledge of the mental health implications of Covid-19, This will help mount an effective response to the current as well as future pandemics., (Copyright © 2020. Published by Elsevier B.V.)

Background: Comparing the course of antipsychotic-naïve psychosis in low- and middle-income countries (LMIC) may help to illuminate core pathophysiologies associated with this condition. Previous reviews-primarily from high-income countries (HIC)-identified cognitive deficits in antipsychotic-naïve, first-episode psychosis, but did not examine whether individuals with psychosis with longer duration of untreated psychosis (DUP > 5 years) were included, nor whether LMIC were broadly represented., Method: A comprehensive search of PUBMED from January 2002-August 2018 identified 36 studies that compared cognitive functioning in antipsychotic-naïve individuals with psychosis (IWP) and healthy controls, 20 from HIC and 16 from LMIC., Results: A key gap was identified in that LMIC study samples were primarily shorter DUP (<5 years) and were primarily conducted in urban China. Most studies matched cases and controls for age and gender but only 9 (24%) had sufficient statistical power for cognitive comparisons. Compared with healthy controls, performance of antipsychotic-naïve IWP was significantly worse in 81.3% (230/283) of different tests of cognitive domains assessed (90.1% in LMIC [118/131] and 73.7% [112/152] in HIC)., Conclusions: Most LMIC studies of cognition in antipsychotic-naïve IWP adopted standardized procedures and, like HIC studies, found broad-based impairments in cognitive functioning. However, these LMIC studies were often underpowered and primarily included samples typical of HIC: primarily male, young-adult, high-school educated IWP, in their first episode of illness with relatively short DUP (<5 years). To enhance understanding of the long-term natural course of cognitive impairments in untreated psychosis, future studies from LMIC should recruit community-dwelling IWP from rural areas where DUP may be longer., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study. We declare that no authors have support from any company for the submitted work. Dr.'s Yang, Phillips, Susser, Keshavan, Stone and Seidman were supported by funds from NIMH R01-MH108385 (PI: Yang) entitled “Characterizing Cognition across the Lifespan in Untreated Psychosis in China.”, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Reduced cortical thickness has been demonstrated in psychotic disorders, but its relationship to clinical symptoms has not been established. We aimed to identify the regions throughout neocortex where clinical psychosis manifestations correlate with cortical thickness. Rather than perform a traditional correlation analysis using total scores on psychiatric rating scales, we applied multidimensional item response theory to identify a profile of psychotic symptoms that was related to a region where cortical thickness was reduced. This analysis was performed using a large population of probands with psychotic disorders (N = 865), their family members (N = 678) and healthy volunteers (N = 347), from the 5-site Bipolar-Schizophrenia Network for Intermediate Phenotypes. Regional cortical thickness from structural magnetic resonance scans was measured using FreeSurfer; individual symptoms were rated using the Positive and Negative Syndrome Scale, Montgomery-Asberg Depression Rating Scale, and Young Mania Rating Scale. A cluster of cortical regions whose thickness was inversely related to severity of psychosis symptoms was identified. The regions turned out to be located contiguously in a large region of heteromodal association cortex including temporal, parietal and frontal lobe regions, suggesting a cluster of contiguous neocortical regions important to psychosis expression. When we tested the relationship between reduced cortical surface area and high psychotic symptoms we found no linked regions describing a related cortical set., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)