Search

OBJECTIVE: Patients with schizophrenia are known to have inhibitory gating deficits in the suppression of evoked potential P50 response to repeated stimuli and the prepulse inhibition of the startle response. In the current study, the authors aimed to determine whether these two inhibitory gating measures are related in schizophrenia patients or whether abnormal P50 suppression and abnormal prepulse inhibition are independent neurophysiological characteristics of schizophrenia. The authors hypothesized that the relationship of the two measures may vary as a function of interstimulus intervals of stimulus presentations. METHOD: Fifty-nine schizophrenia patients and 17 healthy comparison subjects were tested on both P50 suppression and prepulse inhibition. P50 suppression was measured using paired clicks with 500-msec interstimulus intervals. Prepulse inhibition was measured by using a series of prepulse-pulse pairs with interstimulus intervals ranging from 30 to 500 msec. RESULTS: Patients showed reduced P50 suppression and prepulse inhibition in relation to healthy comparison subjects. Concordance analysis showed that abnormal P50 suppression and abnormal prepulse inhibition do not necessarily occur together. Prepulse inhibition was most prominent at the 120-msec interstimulus interval, which was not correlated to P50 suppression. At the 500-msec interstimulus interval, prepulse inhibition was significantly but negatively correlated to P50 suppression. Prepulse inhibition at the other interstimulus intervals was not correlated with P50 suppression. CONCLUSIONS: These neurophysiological measures lack robust and direct relationships and likely mark independent aspects of abnormal brain inhibitory functions in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia Spectrum Disorders (SSDs), which are characterized by social cognitive deficits, have been associated with dysconnectivity in "unimodal" (e.g., visual, auditory) and "multimodal" (e.g., default-mode and frontoparietal) cortical networks. However, little is known regarding how such dysconnectivity relates to social and non-social cognition, and how such brain-behavioral relationships associate with clinical outcomes of SSDs., Methods: We analyzed cognitive (non-social and social) measures and resting-state functional magnetic resonance imaging data from the 'Social Processes Initiative in Neurobiology of the Schizophrenia(s) (SPINS)' study (247 stable participants with SSDs and 172 healthy controls, ages 18-55). We extracted gradients from parcellated connectomes and examined the association between the first 3 gradients and the cognitive measures using partial least squares correlation (PLSC). We then correlated the PLSC dimensions with functioning and symptoms in the SSDs group., Results: The SSDs group showed significantly lower differentiation on all three gradients. The first PLSC dimension explained 68.53% (p<.001) of the covariance and showed a significant difference between SSDs and Controls (bootstrap p<.05). PLSC showed that all cognitive measures were associated with gradient scores of unimodal and multimodal networks (Gradient 1), auditory, sensorimotor, and visual networks (Gradient 2), and perceptual networks and striatum (Gradient 3), which were less differentiated in SSDs. Furthermore, the first dimension was positively correlated with negative symptoms and functioning in the SSDs group., Conclusions: These results suggest a potential role of lower differentiation of brain networks in cognitive and functional impairments in SSDs., (Copyright © 2024. Published by Elsevier Inc.)

Background: Autism and schizophrenia spectrum disorders (SSDs) both feature atypical social cognition. Despite evidence for comparable group-level performance in lower-level emotion processing and higher-level mentalizing, limited research has examined the neural basis of social cognition across these conditions. Our goal was to compare the neural correlates of social cognition in autism, SSDs, and typically developing controls (TDCs)., Methods: Data came from two harmonized studies in individuals diagnosed with autism or SSDs and TDCs (aged 16-35 years), including behavioral social cognitive metrics and two functional magnetic resonance imaging (fMRI) tasks: a social mirroring Imitate/Observe (ImObs) task and the Empathic Accuracy (EA) task. Group-level comparisons, and transdiagnostic analyses incorporating social cognitive performance, were run using FSL's PALM for each task, covarying for age and sex (1000 permutations, thresholded at p < 0.05 FWE-corrected). Exploratory region of interest (ROI)-based analyses were also conducted., Results: ImObs and EA analyses included 164 and 174 participants, respectively (autism N = 56/59, SSD N = 50/56, TDC N = 58/59). EA and both lower- and higher-level social cognition scores differed across groups. While canonical social cognitive networks were activated, no significant whole-brain or ROI-based group-level differences in neural correlates for either task were detected. Transdiagnostically, neural activity during the EA task, but not the ImObs task, was associated with lower- and higher-level social cognitive performance., Limitations: Despite attempting to match our groups on age, sex, and race, significant group differences remained. Power to detect regional brain differences is also influenced by sample size and multiple comparisons in whole-brain analyses. Our findings may not generalize to autism and SSD individuals with co-occurring intellectual disabilities., Conclusions: The lack of whole-brain and ROI-based group-level differences identified and the dimensional EA brain-behavior relationship observed across our sample suggest that the EA task may be well-suited to target engagement in novel intervention testing. Our results also emphasize the potential utility of cross-condition approaches to better understand social cognition across autism and SSDs., (© 2024. The Author(s).)

Background: Preliminary evidence suggests that people with schizophrenia have decreased relative abundance of butyrate-producing bacteria in the gut microbiota. Butyrate plays a critical role in maintaining the integrity of the gut-blood barrier and has a number of anti-inflammatory effects. This proof-of-concept study was designed to assess whether the addition of the oligofructose-enriched inulin (OEI) prebiotic: Prebiotin could increase the production of butyrate., Methods: Twenty-seven people who met the criteria for either Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, schizophrenia or schizoaffective disorder were entered into a 10-day, double-blind, placebo-controlled, randomized clinical trial. The study was conducted on an inpatient unit to standardize the participant diet and environment. Participants were randomized to either OEI (4 g, 3 times a day) or a placebo (4 g of maltodextrin, 3 times a day). In order to assess the effect of OEI treatment on butyrate levels, participants underwent pretreatment and posttreatment OEI challenges. The primary outcome measure was relative change in postchallenge plasma butyrate levels after 10 days of OEI treatment., Results: In both the intent-to-treat and completer analyses, OEI treatment was associated with a greater number of participants who met the OEI challenge responder criteria than those treated with placebo. OEI treatment was also associated with an increase in baseline butyrate levels (effect size for the group difference in the change of baseline butyrate levels was 0.58)., Conclusions: We were able to demonstrate that treatment with the prebiotic OEI selectively increased the level of plasma butyrate in people with schizophrenia.Trial registration:ClinicalTrials.gov identifier NCT03617783., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Fractional amplitude of low-frequency fluctuation (fALFF) is a validated measure of resting-state spontaneous brain activity. Previous fALFF findings in autism and schizophrenia spectrum disorders (ASDs and SSDs) have been highly heterogeneous. We aimed to use fALFF in a large sample of typically developing control (TDC), ASD and SSD participants to explore group differences and relationships with inter-individual variability of fALFF maps and social cognition. fALFF from 495 participants (185 TDC, 68 ASD, and 242 SSD) was computed using functional magnetic resonance imaging as signal power within two frequency bands (i.e., slow-4 and slow-5), normalized by the power in the remaining frequency spectrum. Permutation analysis of linear models was employed to investigate the relationship of fALFF with diagnostic groups, higher-level social cognition, and lower-level social cognition. Each participant's average distance of fALFF map to all others was defined as a variability score, with higher scores indicating less typical maps. Lower fALFF in the visual and higher fALFF in the frontal regions were found in both SSD and ASD participants compared with TDCs. Limited differences were observed between ASD and SSD participants in the cuneus regions only. Associations between slow-4 fALFF and higher-level social cognitive scores across the whole sample were observed in the lateral occipitotemporal and temporoparietal junction. Individual variability within the ASD and SSD groups was also significantly higher compared with TDC. Similar patterns of fALFF and individual variability in ASD and SSD suggest some common neurobiological deficits across these related heterogeneous conditions., Competing Interests: Competing Interest The authors declare no competing interests.

Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas. Participants were clustered based on functioning. Objective II was evaluated in Dataset I by identifying key features for classifying functional phenotype clusters from among 65 sociodemographic, psychological, clinical, cognitive, and brain volume measures. Findings were replicated across latent discriminant analyses (LDA) and one-vs.-rest binomial regularized regressions to identify key predictors. We identified three clusters of participants in each dataset, demonstrating replicable functional phenotypes: Cluster 1-poor functioning across domains; Cluster 2-impaired Role Functioning, but partially preserved Independent and Social Functioning; Cluster 3-good functioning across domains. Key correlates were Avolition, anhedonia, left hippocampal volume, and measures of emotional intelligence and subjective social experience. Avolition appeared more closely tied to role functioning, and anhedonia to independent and social functioning. Thus, we found three replicable functional phenotypes with evidence that recovery may not be uniform across domains. Avolition and anhedonia were both critical but played different roles for different functional domains. It may be important to identify critical functional areas for individual patients and target interventions accordingly., (© 2024. The Author(s).)

Background: Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. The aim of this study was to investigate the relationship between individual variability in functional connectivity during resting state and the performance of a social task and social and non-social cognition in a large sample of controls and individuals diagnosed with SSD., Methods: Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global 'variability score'. Pairwise correlational distance was calculated as 1 - the correlation coefficient between a given pair of participants, and averaging distance from one participant to all other participants provided the mean correlational distance metric. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability., Results: Group comparison between SSD and controls showed greater SSD MCD during rest (p = 0.00038), while no diagnostic differences were observed during task (p = 0.063). Hierarchical regression analyses demonstrated the persistence of a significant diagnostic effect during rest (p = 0.008), contrasting with its non-significance during the task (p = 0.50), after social cognition was added to the model. Notably, social cognition exhibited significance in both resting state and task conditions (both p = 0.01)., Conclusions: Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes., Competing Interests: Declaration of competing interest LDO receives grant support from the Brain & Behavior Research Foundation (BBRF). EWD has received funding from BBRF, National Institute of Mental Health (NIMH), Canadian Institutes of Health Research (CIHR), and Centre for Addiction and Mental Health (CAMH) Foundation. GF currently receives funding from the CIHR, the CAMH Foundation, and the University of Toronto, and has served on an advisory board for AbbVie. AKM receives grant support from the NIMH (R01 MH109508, R01 MH108654, R61 MH120188). RWB has consulted for Boehringer-Ingelheim, serves on the Data Safety and Monitoring Boards of Roche, Merck, and Newron, and has served on the Advisory Boards of Merck, Acadia, Karuna, and Neurocrine. ANV currently receives funding from the NIMH (1/3R01 MH102324, 1/5R01 MH114970), CIHR, Canada Foundation for Innovation, CAMH Foundation, and University of Toronto. CH receives grant support from the NIMH, CIHR, and the CAMH Foundation. All other authors have no interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, but it is markedly underutilized, particularly in the US Black population, partly because of concern over clozapine-associated low absolute neutrophil count (ANC). People of African descent have a lower normative ANC range than the White population, which is associated with a specific "ACKR1-null" ("Duffy null") CC genotype (SNP rs2814778) on the ACKR1 gene, termed benign ethnic neutropenia (BEN). The range of ANC variability and safety of clozapine have not been established in people with BEN or examined prospectively in people of African descent., Methods: We completed a multisite, 6-month, prospective, open-label clinical trial of clozapine treatment in people of African descent with schizophrenia spectrum disorders for whom clozapine was clinically indicated, with or without the ACKR1-null genotype. We examined clozapine safety and weekly ANC during clozapine treatment and evaluated ANC variability by ACKR1-null genotype, sex, study site, and clozapine dosing using repeated measures analysis of covariance. Genotype was assayed using TaqMan® technology., Results: We enrolled 274 participants, of whom 227 (82.8 %) completed 6 months of clozapine treatment. There was one case of severe neutropenia (<500 cells/mm 3 ) (0.36 %) over 1467.6 person-months of clozapine exposure. This participant recovered without sequelae after discontinuation of clozapine. Of the 249 participants with known genotypes, 199 (79.9 %) had the ACKR1-null genotype. Neutropenia (<1500 cells/mm 3 ) occurred significantly more often in the ACKR1-null group (33 % [65/199]) than in those with the T allele (6 % (3/50); p < 0.001). Fourteen (5 %) patients discontinued due to adverse events. Rates of infection and fever were low and sialorrhea was the commonest side effect (N = 187, 68 %)., Conclusion: To our knowledge, this is the largest prospective clozapine trial in people of African descent. Severe neutropenia was rare, despite the high prevalence (80 %) of the ACKR1-null genotype. Our findings suggest that clozapine can be used safely in Black patients including those with BEN., Competing Interests: Declaration of competing interest Dr. Deanna Kelly serves on an advisory board for Alkermes, Teva, and Janssen. Dr. Richard Adebayo has served on the advisory boards of Janssen and a consultant for Invega product. Dr. Raymond Loves serves as a consultant for the Maryland Department of Health and the SMI Advisor, American Psychiatric Association. Dr. Sophie Lanzkron has served as an advisor for Bluebird bio, Novo Nordisk, Pfizer, Novartis and Magenta. She has research funding from Imana, Novartis, GBT, Takeda, CSL-Behring, HRSA, PCORI, MD CHRC. Dr. Robert Buchanan has served on the advisory board for Acadia, Merck and Neurocranial, is a consultant for Boehringer-Ingelheim, and is on DSMB for Merck, Negron, and Roche. All other authors have no conflicts to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tobacco smoking is highly prevalent in persons with psychosis and is the leading cause of preventable mortality in this population. Less is known about tobacco smoking in persons with first episode psychosis (FEP) and there have been no estimates about the prevalence of nicotine vaping in FEP. This study reports rates of tobacco smoking and nicotine vaping in young people with FEP enrolled in Coordinated Specialty Care programs in Pennsylvania and Maryland. Using data collected from 2021 to 2023, we examined lifetime and recent smoking and vaping and compared smokers and vapers to nonusers on symptoms, functioning, and substance use. The sample included 445 participants aged 13-35 with recent psychosis onset. Assessments were collected by program staff. Overall, 28 % of participants engaged in either smoking or vaping within 30 days of the admission assessment. Smokers and vapers were disproportionately male, cannabis users, and had lower negative symptom severity than non-smokers. Vapers had higher role and social functioning. Both smoking and vaping were related to a longer time from psychosis onset to program enrollment. We compare these findings to previous studies and suggest steps for addressing smoking and vaping in this vulnerable population., Competing Interests: Declaration of competing interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis., (© 2024 World Psychiatric Association.)

Background: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder., Methods: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation., Findings: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented., Interpretation: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores., Funding: German Research Foundation (grant number: 428509362)., Competing Interests: Declaration of interests RAM has received speaker or consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. JMK has been a consultant or advisor for, or has received honoraria from, Alkermes, Allergan, LB Pharmaceuticals, H Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson & Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva, and UpToDate, and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. CA has been a consultant to, or has received honoraria or grants from, Acadia, Abbot, Ambrosetti, AMGEN, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forum, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sunovion, and Takeda. WWF has received consulting fees from Boehringer Ingelheim, Angelini, Richter, and Recordati, and grant support from Lundbeck and Otsuka. PF received paid speakership from Otsuka, Recordati, Richter, Rovi, and Janssen, and is a member of advisory boards of Richter, Rovi, and Janssen. AH has received paid speakerships from AbbVie, Janssen, Otsuka, Rercordati, and Lundbeck. He was member of Rovi, Recordati, Otsuka, Lundbeck, and Janssen advisory boards. SRM has received consulting fees from Boehringer-Ingelheim, H. Lundbeck, Otsuka, Takeda, Teva, Roche, Genentech, Targacept, Forum, AbbVie, Allergan, and Neurocrine. He has received research support from Boehringer-Ingelheim, Takeda, and Neurocrine. NS has been a consultant or advisor to, or has received honoraria, from Alkermes, Lundbeck, Otsuka, Otsuka Canada, and Teva. WGH has received consulting fees or sat on paid advisory boards for In Silico Biosciences, Translational Life Sciences, Newron, Otsuka, and AbbVie. RWB is a data and safety monitoring board member for Merck, Newron, and Roche; on the advisory board for Acadia, Boehringer Ingelheim, Karuna, Neurocrine, and Roche; and consultant for Boehringer Ingelheim. MD is an employee of Minerva Neurosciences. MW He has received advisory board, speaker's, or consultant fees from, and owns stock, with Acadia, Dexcel, Janssen, Lundbeck, Minerva, Pfizer, Roche, and Teva. OH was a part-time employee of H. Lundbeck, and has received investigator-initiated research funding from, or participated in, advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris/Mylan. Neither he nor his family have holdings/a financial stake in any pharmaceutical company. He has a patent for the use of dopaminergic imaging. CUC has been a consultant or advisor to, or has received honoraria from, AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantics. In the past 3 years, SL has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Hypothesis: Neurocognitive and social cognitive abilities are important contributors to functional outcomes in schizophrenia spectrum disorders (SSDs). An unanswered question of considerable interest is whether neurocognitive and social cognitive deficits arise from overlapping or distinct white matter impairment(s)., Study Design: We sought to fill this gap, by harnessing a large sample of individuals from the multi-center Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) dataset, unique in its collection of advanced diffusion imaging and an extensive battery of cognitive assessments. We applied canonical correlation analysis to estimates of white matter microstructure, and cognitive performance, across people with and without an SSD., Study Results: Our results established that white matter circuitry is dimensionally and strongly related to both neurocognition and social cognition, and that microstructure of the uncinate fasciculus and the rostral body of the corpus callosum may assume a "privileged role" subserving both. Further, we found that participant-wise estimates of white matter microstructure, weighted by cognitive performance, were largely consistent with participants' categorical diagnosis, and predictive of (cross-sectional) functional outcomes., Conclusions: The demonstrated strength of the relationship between white matter circuitry and neurocognition and social cognition underscores the potential for using relationships among these variables to identify biomarkers of functioning, with potential prognostic and therapeutic implications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975)., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Learning Objective After Participating in This Cme Activity, the Psychiatrist Should Be Better Able to: • Outline and Identify potential benefits of using neurological soft signs (NSS) as biomarkers of schizophrenia., Abstract: Since the late 1960s, NSS have been a focus of study across psychiatric illnesses, including depression, bipolar disorder, and schizophrenia in particular. Utilizing these subtle neurological impairments as biomarkers of illness has numerous benefits; NSS offer a direct connection between clinical presentation and neurological functioning, and assessments are cost-effective. However, incongruent measurement scales, confounding variables, and rating system subjectivity have hindered the advancement and scalability of NSS research and clinical implementation. This article provides a brief overview of the literature on NSS as related to schizophrenia, and proposes utilizing smartphone sensing technology to create standardized NSS assessments with objective scoring. Incorporating digital phenotyping into NSS assessment offers the potential to make measurement more scalable, accessible, and directly comparable across locations, cultures, and demographics. We conducted a narrative search in PubMed and APA PsycInfo using the following keywords: neurological soft signs, schizophrenia spectrum disorders, and psychotic illnesses. No date limitations were used. There is no other direct work on NSS and new smartphone methods like digital phenotyping; though, there is related work in neurology. Harnessing advances in smartphone technology could provide greater insight into and further our understanding of specific aspects of the NSS field. For instance, it could help us distinguish trait vs. state markers and better understand how distinct groups of signs may reflect different aspects of psychiatric illness and neurological impairment. In addition, such technology can help advance research on the capabilities of NSS as an effective diagnostic tool., (Copyright © 2023 President and Fellows of Harvard College.)

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15-58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Structural neuroimaging studies have identified similarities in the brains of individuals diagnosed with schizophrenia (SZ) and bipolar I disorder (BP), with overlap in regions of gray matter (GM) deficits between the two disorders. Recent studies have also shown that the symptom phenotypes associated with SZ and BP may allow for a more precise categorization than the current diagnostic criteria. In this study, we sought to identify GM alterations that were unique to each disorder and whether those alterations were also related to unique symptom profiles., Materials and Methods: We analyzed the GM patterns and clinical symptom presentations using independent component analysis (ICA), hierarchical clustering, and n-way biclustering in a large ( N ∼ 3,000), merged dataset of neuroimaging data from healthy volunteers (HV), and individuals with either SZ or BP., Results: Component A showed a SZ and BP < HV GM pattern in the bilateral insula and cingulate gyrus. Component B showed a SZ and BP < HV GM pattern in the cerebellum and vermis. There were no significant differences between diagnostic groups in these components. Component C showed a SZ < HV and BP GM pattern bilaterally in the temporal poles. Hierarchical clustering of the PANSS scores and the ICA components did not yield new subgroups. N-way biclustering identified three unique subgroups of individuals within the sample that mapped onto different combinations of ICA components and symptom profiles categorized by the PANSS but no distinct diagnostic group differences., Conclusion: These multivariate results show that diagnostic boundaries are not clearly related to structural differences or distinct symptom profiles. Our findings add support that (1) BP tend to have less severe symptom profiles when compared to SZ on the PANSS without a clear distinction, and (2) all the gray matter alterations follow the pattern of SZ < BP < HV without a clear distinction between SZ and BP., 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 © 2022 Rootes-Murdy, Edmond, Jiang, Rahaman, Chen, Perrone-Bizzozero, Calhoun, van Erp, Ehrlich, Agartz, Jönsson, Andreassen, Westlye, Wang, Pearlson, Glahn, Hong, Buchanan, Kochunov, Voineskos, Malhotra, Tamminga, Liu and Turner.)

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)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP is metabolized to serotonin and further to 5-hydroxyindoleacetic acid (5-HIAA). Notably, KP metabolism is readily affected by immune stimulation. Here, we assessed the acute effects of an oral TRP challenge (6 g) on peripheral concentrations of kynurenine, KYNA and 5-HIAA, as well as the cytokines interferon-γ, TNF-α and interleukin-6, in 22 participants with SZ and 16 healthy controls (HCs) using a double-blind, placebo-controlled, crossover design. TRP raised the levels of kynurenine, KYNA and 5-HIAA in a time-dependent manner, causing >20-fold, >130-fold and 1.5-fold increases in kynurenine, KYNA and 5-HIAA concentrations, respectively, after 240 min. According to multivariate analyses, neither baseline levels nor the stimulating effects of TRP differed between participants with SZ and HC. Basal cytokine levels did not vary between groups, and remained unaffected by TRP. Although unlikely to be useful diagnostically, measurements of circulating metabolites following an acute TRP challenge may be informative for assessing the in vivo efficacy of drugs that modulate the neosynthesis of KYNA and other products of TRP degradation.

Schizophrenia is a severe mental disorder with various medical comorbidities and early mortality. Hyperprolactinemia is common in women and its impact on sexual function, galactorrhea and amenorrhea is well known. This paper evaluates the risk of 25-hydroxy vitamin D deficiency and other metabolic related laboratory abnormalities in women with schizophrenia having hyperprolactinemia (N = 43). The mean prolactin level in these women was 88.5 ± 56.0 ng/mL. We found that 100% of women were overweight of which 74% (32/43) of the women were obese, 56% (23/41) had abnormal total cholesterol levels and 30% (13/43) had high fasting blood glucose. Vitamin D levels were considered deficient or inadequate in 37% of women. We did not see significant correlations of prolactin with laboratory measures, however all female patients had elevated and high prolactin levels, leading to low variability in a small sample, which may have precluded seeing any direct relationships. Recognizing prolactin related side effects and understanding the role of other health measures seen in women with antipsychotic induced hyperprolactinemia in our female patients are critical steps toward better personalization of their care and recovery., (Copyright © 2022. Published by Elsevier Ltd.)

Human neuroimaging has led to an overwhelming amount of research into brain function in healthy and clinical populations. However, a better appreciation of the limitations of small sample studies has led to an increased number of multi-site, multi-scanner protocols to understand human brain function. As part of a multi-site project examining social cognition in schizophrenia, a group of "travelling human phantoms" had structural T1, diffusion, and resting-state functional MRIs obtained annually at each of three sites. Scan protocols were carefully harmonized across sites prior to the study. Due to scanner upgrades at each site (all sites acquired PRISMA MRIs during the study) and one participant being replaced, the end result was 30 MRI scans across 4 people, 6 MRIs, and 4 years. This dataset includes multiple neuroimaging modalities and repeated scans across six MRIs. It can be used to evaluate differences across scanners, consistency of pipeline outputs, or test multi-scanner harmonization approaches., (© 2022. The Author(s).)

Social cognitive impairments are core features of schizophrenia spectrum disorders (SSD) and are associated with greater functional impairment and decreased quality of life. Metabolic disturbances have been related to greater impairment in general neurocognition, but their relationship to social cognition has not been previously reported. In this study, metabolic measures and social cognition were assessed in 245 participants with SSD and 165 healthy comparison subjects (HC), excluding those with hemoglobin A1c (HbA1c) > 6.5%. Tasks assessed emotion processing, theory of mind, and social perception. Functional connectivity within and between social cognitive networks was measured during a naturalistic social task. Among SSD, a significant inverse relationship was found between social cognition and cumulative metabolic burden (β = -0.38, p < 0.001) and HbA1c (β = -0.37, p < 0.001). The relationship between social cognition and HbA1c was robust across domains and measures of social cognition and after accounting for age, sex, race, non-social neurocognition, hospitalization, and treatment with different antipsychotic medications. Negative connectivity between affect sharing and motor resonance networks was a partial mediator of this relationship across SSD and HC groups (β = -0.05, p = 0.008). There was a group x HbA1c effect indicating that SSD participants were more adversely affected by increasing HbA1c. Thus, we provide the first report of a robust relationship in SSD between social cognition and abnormal glucose metabolism. If replicated and found to be causal, insulin sensitivity and blood glucose may present as promising targets for improving social cognition, functional outcomes, and quality of life in SSD., (© 2022. The Author(s).)

Objectives: Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms., Methods: Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3)., Results: SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples., Conclusions: Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints., (© The Author(s) 2022. 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: Difficulties in social cognition are common in individuals with schizophrenia (SZ) and are not ameliorated by antipsychotic treatment. Intranasal oxytocin (OT) administration has been explored as a potential intervention to improve social cognition; however, results are inconsistent, suggesting potential individual difference variables that may influence treatment response. Less is known about the relationship between endogenous OT and social cognition in SZ, knowledge of which may improve the development of OT-focused therapies. We examined plasma OT in relationship to facial emotion recognition and visual attention to salient facial features in SZ and controls., Methods: Forty-two individuals with SZ and 23 healthy controls viewed photographs of facial expressions of varying emotional intensity and identified the emotional expression displayed. Participants' gaze behavior during the task was recorded via eye tracking. Plasma oxytocin concentrations were determined by radioimmunoassay., Results: SZ were less accurate than controls at identifying high-intensity fearful facial expressions and low-intensity sad expressions. Lower overall and high-intensity facial emotion recognition accuracy was associated with lower plasma OT levels in SZ but not controls. OT was not associated with visual attention to salient facial features; however, SZ had reduced visual attention to the nose region compared to controls., Conclusion: Individual differences in endogenous OT predict facial emotion recognition ability in SZ but are not associated with visual attention to salient facial features. Increased understanding of the association between endogenous OT and social cognitive abilities in SZ may help improve the design and interpretation of OT-focused clinical trials in SZ., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Outcomes for individuals with psychotic disorders can be improved through early intervention services; however, identification continues to be a major problem in connecting individuals with these services. Social workers form a vast majority of the human service and mental health workforce in the United States and therefore have the potential to play a unique role in identifying and referring those who may benefit from specialty early intervention services., Methods: The current article describes the methodological design, implementation, and participant recruitment procedures of a large-scale, web-based training program for social workers promoting identification and referral of individuals with emerging symptoms of a mental illness with psychosis in the context of a randomized clinical trial., Results: The web-based study enrolled 1384 individuals. More than half of study participants enrolled within the first 3 months of the 14-month recruitment period. Completion of all study components was achieved by 959 individuals (69% of total enrolled), and completion status did not vary significantly by gender, ethnicity, or facility at which the individual was employed. Completion rates varied by race, such that participants identifying as White were more likely to complete the study, while those identifying as Black were less likely., Discussion: The results suggest the feasibility of using a web-based training program to engage social workers in early psychosis identification practices. Challenges related to encouraging participants to complete the training and lessons learned during the study recruitment are discussed., (© 2021 John Wiley & Sons Australia, Ltd.)

Sedentary behavior contributes to a shortened life expectancy in individuals with schizophrenia-spectrum disorders (SSDs), highlighting the need for effective interventions to improve health. This study examined whether reduced ecological momentary assessment (EMA) measures of sedentary activities were observed in individuals with SSDs who participated in a 24-week randomized trial of cognitive behavioral social skills training (CBSST) and either intranasal oxytocin or placebo (NCT01752712). Participants ( n = 57) were prompted with EMA surveys seven times per day for seven days during the baseline, 12-week, and 24-week timepoints to sample sedentary behavior ratings, positive and negative affect, interpersonal interactions, and interpersonal interaction appraisals. Results revealed that sedentary behavior and social interactions did not significantly change over the 24-week clinical trial; however, positive and negative affect and defeatist interaction appraisals improved with treatment, and oxytocin produced modest additional improvements in these EMA outcomes. Greater momentary positive affect was significantly associated with greater activity and greater frequency of interactions. Overall, CBSST was effective at improving functioning, momentary affect, and defeatist interaction appraisals, although it did not reduce sedentary behavior; therefore, targeting these factors is not sufficient to reduce sedentary behavior, and adjunct interventions are needed.

Background: Schizophrenia spectrum disorders (SSDs) feature social cognitive deficits, although their neural basis remains unclear. Social cognitive performance may relate to neural circuit activation patterns more than to diagnosis, which would have important prognostic and therapeutic implications. The current study aimed to determine how functional connectivity within and between social cognitive networks relates to social cognitive performance across individuals with SSDs and healthy control participants., Methods: Participants with SSDs (n = 164) and healthy control participants (n = 117) completed the Empathic Accuracy task during functional magnetic resonance imaging as well as lower-level (e.g., emotion recognition) and higher-level (e.g., theory of mind) social cognitive measures outside the scanner. Functional connectivity during the Empathic Accuracy task was analyzed using background connectivity and graph theory. Data-driven social cognitive networks were identified across participants. Regression analyses were used to examine network connectivity-performance relationships across individuals. Positive and negative within- and between-network connectivity strengths were also compared in poor versus good social cognitive performers and in SSD versus control groups., Results: Three social cognitive networks were identified: motor resonance, affect sharing, and mentalizing. Regression and group-based analyses demonstrated reduced between-network negative connectivity, or segregation, and greater within- and between-network positive connectivity in worse social cognitive performers. There were no significant effects of diagnostic group on within- or between-network connectivity., Conclusions: These findings suggest that the neural circuitry of social cognitive performance may exist dimensionally. Across participants, better social cognitive performance was associated with greater segregation between social cognitive networks, whereas poor versus good performers may compensate via hyperconnectivity within and between social cognitive networks., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL., (© 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: Effectiveness of antipsychotic drugs is inferred from relatively small randomized clinical trials conducted with carefully selected and monitored participants. This evidence is not necessarily generalizable to individuals treated in daily clinical practice. The authors compared the clinical effectiveness between all oral and long-acting injectable (LAI) antipsychotic medications used in the treatment of schizophrenia in the U.S. Department of Veterans Affairs (VA) health care system., Methods: This was an observational study utilizing VA pharmacy data from 37,368 outpatient veterans with schizophrenia. Outcome measures were all-cause antipsychotic discontinuation and psychiatric hospitalizations. Oral olanzapine was used as the reference group., Results: In multivariable analysis, clozapine (hazard ratio=0.43), aripiprazole long-acting injectable (LAI) (hazard ratio=0.71), paliperidone LAI (hazard ratio=0.76), antipsychotic polypharmacy (hazard ratio=0.77), and risperidone LAI (hazard ratio=0.91) were associated with reduced hazard of discontinuation compared with oral olanzapine. Oral first-generation antipsychotics (hazard ratio=1.16), oral risperidone (hazard ratio=1.15), oral aripiprazole (hazard ratio=1.14), oral ziprasidone (hazard ratio=1.13), and oral quetiapine (hazard ratio=1.11) were significantly associated with an increased risk of discontinuation compared with oral olanzapine. No treatment showed reduced risk of psychiatric hospitalization compared with oral olanzapine; quetiapine was associated with a 36% worse outcome in terms of hospitalizations compared with olanzapine., Conclusions: In a national sample of veterans with schizophrenia, those treated with clozapine, two of the LAI second-generation antipsychotics, and antipsychotic polypharmacy continued the same antipsychotic therapy for a longer period of time compared with the reference drug. This may reflect greater overall acceptability of these medications in clinical practice.

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.)

White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) "Which clinical variables explain WM abnormalities?". (2) "Does the degree of WM abnormalities predict symptom severity?". (3) "Does sex influence any of those relationships?". Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: A significant proportion of people with schizophrenia are characterized by impaired ability to socially engage with others. The development of effective interventions for social functioning remains a central therapeutic challenge. Cognitive-behavioral social skills training (CBSST) has been found to improve social functioning in schizophrenia, but with only medium effect sizes. Intranasal oxytocin also has prosocial effects, but also only with modest effect sizes. This study assessed whether the addition of intranasal oxytocin to CBSST can strengthen their impact on social function., Methods: Participants (N = 62) with schizophrenia or schizoaffective disorder entered a 24-week, double-blind, placebo-controlled, randomized clinical trial with a 3-month follow-up evaluation at 2 sites: Maryland and San Diego. Participants were randomized to either intranasal oxytocin 36 IU (3 sprays) twice a day (n = 31) or intranasal placebo-oxytocin (3 sprays) twice a day (n = 31). All participants received CBSST plus a social cognition skills training module (48 total sessions)., Results: There were no significant treatment group differences in social functioning, positive symptoms, negative symptoms, defeatist beliefs, or asocial beliefs. The interpretation of treatment effects was complicated by site effects, whereby participants in San Diego began the trial with greater severity of impairments and subsequently showed greater improvements compared with participants in Maryland., Conclusions: The results did not support the utility of add-on intranasal oxytocin to psychosocial rehabilitation interventions like CBSST for improvement in social function (ClinicalTrials.gov trial number: NCT01752712)., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Axonal myelination and repair, critical processes for brain development, maturation, and aging, remain controlled by sexual hormones. Whether this influence is reflected in structural brain differences between sexes, and whether it can be quantified by neuroimaging, remains controversial. Diffusion-weighted magnetic resonance imaging (dMRI) is an in vivo method that can track myelination changes throughout the lifespan. We utilize a large, multisite sample of harmonized dMRI data (n = 551, age = 9-65 years, 46% females/54% males) to investigate the influence of sex on white matter (WM) structure. We model lifespan trajectories of WM using the most common dMRI measure fractional anisotropy (FA). Next, we examine the influence of both age and sex on FA variability. We estimate the overlap between male and female FA and test whether it is possible to label individual brains as male or female. Our results demonstrate regionally and spatially specific effects of sex. Sex differences are limited to limbic structures and young ages. Additionally, not only do sex differences diminish with age, but tracts within each subject become more similar to one another. Last, we show the high overlap in FA between sexes, which implies that determining sex based on WM remains open., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Abnormal reward processing is thought to play an important role in the development of psychosis, but relatively few studies have examined reward prediction errors, reinforcement learning (RL), and the reward circuitry that subserves these interconnected processes among individuals at clinical high-risk (CHR) for the disorder. Here, we present behavioral and functional neuroimaging results of two experimental tasks designed to measure overlapping aspects of reward processing among individuals at CHR (n = 22) and healthy controls (n = 19). We found no group differences in response times to positive, negative, or neutral outcome-signaling cues, and no significant differences in brain activation during reward anticipation or receipt. Youth at CHR, however, displayed clear RL impairments, as well as attenuated responses to rewards and blunted prediction error signals in the ventral striatum, dorsal anterior cingulate cortex (dACC), and ventromedial prefrontal cortex (vmPFC). Greater contrasts for cue valence (gain-loss) and outcome magnitude (large-small) in the vmPFC were associated with more severe negative symptoms, and deficits in dACC signaling during RL were associated with more depressive symptoms. Our results provide evidence for RL deficits and abnormal prediction error signaling in the brain's reward circuitry among individuals at CHR, while also suggesting that reward motivation may be relatively preserved at this stage in development. Longitudinal studies, medication-free participants, and comparison of neurobehavioral measures against both healthy and clinical controls are needed to better understand the role of reward system abnormalities in the development of psychosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.

Background: Despite adequate antipsychotic treatment, most people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. The current study was designed to examine the efficacy and safety of adjunctive anti-inflammatory combination therapy for these illness manifestations., Methods: Thirty-nine people with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, schizophrenia or schizoaffective disorder were entered into a 12-week double-blind, 2-arm, triple-dummy, placebo-controlled, randomized clinical trial: 19 were randomized to anti-inflammatory combination therapy and 20 were randomized to placebo. The Brief Psychiatric Rating Scale positive symptom item total score was used to assess positive symptom change, the Scale for the Assessment of Negative Symptoms total score was used to assess negative symptom change, the Calgary Depression Scale total score was used to assess depressive symptom change, and the MATRICS Consensus Cognitive Battery was used to assess neuropsychological test performance., Results: There was a significant time effect for Brief Psychiatric Rating Scale positive symptom item score (t226 = -2.66, P = 0.008), but the treatment (t54=1.52, P = 0.13) and treatment × time (t223 = 0.47, P = 0.64) effects were not significant. There were no significant time (t144 = 0.53, P = 0.72), treatment (t58=0.48, P = 0.63), or treatment × time (t143 = -0.20, P = 0.84) effects for the Scale for the Assessment of Negative Symptoms total score; or for any of the other symptom measures. There were no significant group differences in the change in the MATRICS Consensus Cognitive Battery composite score over the course of the study (F1,26=2.20, P = 0.15)., Conclusions: The study results suggest that there is no significant benefit of combined anti-inflammatory treatment for persistent positive symptoms or negative symptoms or cognitive impairments (clinicaltrials.gov trial number: NCT01514682).

Early detection and prevention of psychosis has become an international priority. Much of this work has focused on youth presenting with attenuated symptoms of psychosis-those at Clinical High Risk for psychosis (CHR)-given their elevated probability of developing the full disorder in subsequent years. Individuals at CHR may be prone to exacerbated psychological distress during the COVID-19 pandemic and its subsequent physical isolation measures, due to heightened stress sensitivity and comorbid mental health problems. Telepsychotherapy holds promise for reaching this population, especially during the current COVID-19 outbreak. However, there are limited evidence-based guidelines or interventions for use of telepsychotherapy with this population. In this paper, we review common clinical issues for individuals at CHR and how they might be exacerbated by the COVID-19 pandemic; best practices for treatment and adaptations for telepsychotherapy for individuals at CHR; and highlight real clinical issues that we are currently experiencing in a United States-based specialized CHR clinic as we conduct telepsychotherapy via videoconferencing. We conclude with questions for those in the field to contemplate, as well as potential challenges and benefits in using telepsychotherapy with individuals at CHR and their families.