Assessing social cognition in patients with schizophrenia and healthy controls using the reading the mind in the eyes test (RMET): a systematic review and meta-regression.

The reading the mind in the eyes test (RMET) - which assesses the theory of mind component of social cognition - is often used to compare social cognition between patients with schizophrenia and healthy controls. There is, however, no systematic review integrating the results of these studies. We identified 198 studies published before July 2020 that administered RMET to patients with schizophrenia or healthy controls from three English-language and two Chinese-language databases. These studies included 41 separate samples of patients with schizophrenia (total n = 1836) and 197 separate samples of healthy controls (total n = 23 675). The pooled RMET score was 19.76 (95% CI 18.91-20.60) in patients and 25.53 (95% CI 25.19-25.87) in controls (z = 12.41, p < 0.001). After excluding small-sample outlier studies, this difference in RMET performance was greater in studies using non-English v. English versions of RMET (Chi [Q] = 8.54, p < 0.001). Meta-regression analyses found a negative association of age with RMET score and a positive association of years of schooling with RMET score in both patients and controls. A secondary meta-analysis using a spline construction of 180 healthy control samples identified a non-monotonic relationship between age and RMET score - RMET scores increased with age before 31 and decreased with age after 31. These results indicate that patients with schizophrenia have substantial deficits in theory of mind compared with healthy controls, supporting the construct validity of RMET as a measure of social cognition. The different results for English versus non-English versions of RMET and the non-monotonic relationship between age and RMET score highlight the importance of the language of administration of RMET and the possibility that the relationship of aging with theory of mind is different from the relationship of aging with other types of cognitive functioning.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis.

INTRODUCTION: High-inflammation subgroups of patients with psychosis demonstrate cognitive deficits and neuroanatomical alterations. Systemic inflammation assessed using IL-6 and C-reactive protein may alter functional connectivity within and between resting-state networks, but the cognitive and clinical implications of these alterations remain unknown. We aim to determine the relationships of elevated peripheral inflammation subgroups with resting-state functional networks and cognition in psychosis spectrum disorders. METHODS: Serum and resting-state fMRI were collected from psychosis probands (schizophrenia, schizoaffective, psychotic bipolar disorder) and healthy controls (HC) from the B-SNIP1 (Chicago site) study who were stratified into inflammatory subgroups based on factor and cluster analyses of 13 cytokines (HC Low n = 32, Proband Low n = 65, Proband High n = 29). Nine resting-state networks derived from independent component analysis were used to assess functional and multilayer connectivity. Inter-network connectivity was measured using Fisher z-transformation of correlation coefficients. Network organization was assessed by investigating networks of positive and negative connections separately, as well as investigating multilayer networks using both positive and negative connections. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia. Linear regressions, Spearman correlations, permutations tests and multiple comparison corrections were used for analyses in R. RESULTS: Anterior default mode network (DMNa) connectivity was significantly reduced in the Proband High compared to Proband Low (Cohen's d = -0.74, p = 0.002) and HC Low (d = -0.85, p = 0.0008) groups. Inter-network connectivity between the DMNa and the right-frontoparietal networks was lower in Proband High compared to Proband Low (d = -0.66, p = 0.004) group. Compared to Proband Low, the Proband High group had lower negative (d = 0.54, p = 0.021) and positive network (d = 0.49, p = 0.042) clustering coefficient, and lower multiplex network participation coefficient (d = -0.57, p = 0.014). Network findings in high inflammation subgroups correlate with worse verbal fluency, verbal memory, symbol coding, and overall cognition. CONCLUSION: These results expand on our understanding of the potential effects of peripheral inflammatory signatures and/or subgroups on network dysfunction in psychosis and how they relate to worse cognitive performance. Additionally, the novel multiplex approach taken in this study demonstrated how inflammation may disrupt the brain's ability to maintain healthy co-activation patterns between the resting-state networks while inhibiting certain connections between them.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Functional connectivity associated with improvement in emotion management after cognitive enhancement therapy in early-course schizophrenia.

BACKGROUND: The ability to manage emotions is an important social-cognitive domain impaired in schizophrenia and linked to functional outcome. The goal of our study was to examine the impact of cognitive enhancement therapy (CET) on the ability to manage emotions and brain functional connectivity in early-course schizophrenia. METHODS: Participants were randomly assigned to CET (n = 55) or an enriched supportive therapy (EST) control group (n = 45). The resting-state functional magnetic resonance imaging scans and measures of emotion management performances were collected at baseline, 9, and 18 months follow-up. The final sample consisted of 37 CET and 25 EST participants, including 19 CET and 12 EST participants with imaging data. Linear mixed-effects models investigated the impact of treatment on emotion management and functional connectivity from the amygdala to ventrolateral and dorsolateral prefrontal cortex (dlPFC). RESULTS: The CET group showed significant improvement over time in emotion management compared to EST. Neither functional connectivity changes nor main group differences were observed following treatment. However, a significant between-group interaction showed that improved emotion management ability was associated with increased functional connectivity between the left amygdala and the left dlPFC in the CET group exclusively. CONCLUSION: Our results replicate the previous work demonstrating that CET is effective at improving some aspects of social cognition in schizophrenia. We found evidence that improvement in emotion management may be associated with a change in amygdala-dlPFC connectivity. This fronto-limbic circuit may provide a mechanistic link between the biology of emotion management processes that can be enhanced in individuals with schizophrenia.

Antisaccade error rates and gap effects in psychosis syndromes from bipolar-schizophrenia network for intermediate phenotypes 2 (B-SNIP2).

BACKGROUND: Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes. METHODS: Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns. RESULTS: Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups. CONCLUSIONS: With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.

GWAS significance thresholds for deep phenotyping studies can depend upon minor allele frequencies and sample size.

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.

Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis.

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.

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis.

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 (FAT) 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 FAT in adolescence, and 4% lower FAT 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 FAT 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.

Cognitive Enhancement Therapy vs social skills training in schizophrenia: a cluster randomized comparative effectiveness evaluation.

BACKGROUND: Schizophrenia and related disorders are highly disabling and create substantial burdens for families, communities, and health care systems. Although pharmacological treatments can often lessen the psychotic symptoms that are a hallmark of schizophrenia, they do not lessen the social and cognitive deficits that create the greatest impediments to community engagement and functional recovery. This study builds on prior research on psychosocial rehabilitation by comparing the effectiveness of two treatments demonstrated as efficacious in improving social and community functioning, Cognitive Enhancement Therapy (CET) and a version of Social Skills Training (HOPES/SST). METHODS: The study uses a randomized cluster design in which a pair of clinicians at community- and hospital-based mental service centers deliver either CET or HOPES to at least one group of 6-8 eligible clients for 12 months. Clinicians are trained and then supervised weekly, with ongoing process measurement of treatment fidelity, attendance, satisfaction, and retention, and use of other services. Measures administered at baseline and at 6 and 12 months while in treatment, and then at 18 and 24 months after treatment include social adjustment, quality of life, social skills, positive and negative symptoms, and neuro- and social cognition. We hypothesize that CET will be associated with greater improvements than SST in both the primary outcome of community functioning and the secondary outcomes of neuro- and social cognition and social skills. Secondarily, we hypothesize that more cognitive impairment at baseline and younger age will predict more benefit from CET compared to HOPES. DISCUSSION: Resource shortages endemic in mental health services and exacerbated by the pandemic highlight the importance of identifying the most effective approach to improving social and community functioning. We aim to improve understanding of the impact of two efficacious psychosocial treatments and to improve clinicians' ability to refer to both treatments the individuals who are most likely to benefit from them. We expect the result to be programmatic improvements that improve the magnitude and durability of gains in community functioning. TRIAL REGISTRATION: ClinicalTrial.gov NCT04321759 , registered March 25, 2020.

Premorbid Sociality Moderates Social Adjustment Change during Cognitive Enhancement Therapy for Adults with Early Schizophrenia.

OBJECTIVE: Cognitive remediation approaches for early course schizophrenia are promising interventions for improving social adjustment. Premorbid sociality is a potentially important moderator of social adjustment response to cognitive remediation and may serve to personalize such interventions. METHOD: Eighty-eight early course schizophrenia outpatients with premorbid sociality scores were included in this preliminary investigation. Secondary data came from a recent 18-month multi-site confirmatory trial of Cognitive Enhancement Therapy (CET) compared to Enriched Supportive Therapy (EST). Intent-to-treat mixed effects models examined the moderating effect of premorbid sociality assessed at baseline on differential social adjustment change between CET and EST assessed at baseline, 9, and 18 months. RESULTS: Premorbid sociality significantly moderated the differential effect of CET vs. EST on overall social adjustment change at 18 months, such that CET was particularly effective for patients with high premorbid sociality and EST for low premorbid sociality. This significant group x time x premorbid sociality interaction was also observed for 18-month change in interpersonal anguish, self-care, and sexual relations. Again, CET was largely favorable for higher premorbid sociality patients and EST for lower premorbid sociality for these sub-scales. CONCLUSIONS: The results provide initial evidence that premorbid sociality moderates differential social adjustment change during cognitive remediation in early course schizophrenia. In many, but not all cases, better social functioning prior to the development of schizophrenia was associated with a significantly better social adjustment response to CET. Data on social functioning during childhood and adolescence is possibly useful for personalizing treatment planning in the early course of schizophrenia.

Regression dynamic causal modeling for resting-state fMRI.

"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.

Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.

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.

Calculating individualized risk components using a mobile app-based risk calculator for clinical high risk of psychosis: findings from ShangHai At Risk for Psychosis (SHARP) program.

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.

Comparison of social cognition using an adapted Chinese version of the Reading the Mind in the Eyes Test in drug-naive and regularly medicated individuals with chronic schizophrenia and healthy controls in rural China.

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.

Individualized risk components guiding antipsychotic delivery in patients with a clinical high risk of psychosis: application of a risk calculator.

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.

Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program.

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.