Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Validation of an ICD-code-based case definition for psychotic illness across three health systems.

Background and Hypothesis: Early detection of psychosis is critical for improving outcomes. Algorithms to predict or detect psychosis using electronic health record (EHR) data depend on the validity of the case definitions used, typically based on diagnostic codes. Data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. Study Design: Using EHRs at three health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into five higher-order groups. 1,133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. Study Results: PPVs across all diagnostic groups and hospital systems exceeded 70%: Massachusetts General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). Conclusions: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders.

Although there is convergent evidence for blood-brain barrier (BBB) dysfunction and peripheral inflammation in schizophrenia (SZ) and bipolar disorder (BD), it is unknown whether BBB deficits are intrinsic to brain microvascular endothelial cells (BMECs) or arise via effects of peripheral inflammatory cytokines. We examined BMEC function using stem cell-based models to identify cellular and molecular deficits associated with BBB dysfunction in SZ and BD. Induced pluripotent stem cells (iPSCs) from 4 SZ, 4 psychotic BD and 4 healthy control (HC) subjects were differentiated into BMEC-"like" cells. Gene expression and protein levels of tight junction proteins were assessed. Transendothelial electrical resistance (TEER) and permeability were assayed to evaluate BBB function. Cytokine levels were measured from conditioned media. BMECs derived from human iPSCs in SZ and BD did not show differences in BBB integrity or permeability compared to HC BMECs. Outlier analysis using TEER revealed a BBB-deficit (n = 3) and non-deficit (n = 5) group in SZ and BD lines. Stratification based on BBB function in SZ and BD patients identified a BBB-deficit subtype with reduced barrier function, tendency for increased permeability to smaller molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased matrix metallopeptidase 1 (MMP1) activity, which correlated with reduced CLDN5 and worse BBB function, and was improved by tumor necrosis factor α (TNFα) and MMP1 inhibition. These results show potential deficits in BMEC-like cells in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as promising targets for ameliorating BBB deficits.

Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.

BACKGROUND: Postmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia. METHODS: We generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia. RESULTS: Cortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits. CONCLUSIONS: Taken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.

Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder.

We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder. Supplementary Information: The online version contains supplementary material available at 10.1007/s44192-023-00031-8.

Human stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review.

Cognitive impairment is the strongest predictor of functional outcomes in schizophrenia and is hypothesized to result from synaptic dysfunction. However, targeting synaptic plasticity and cognitive deficits in patients remains a significant clinical challenge. A comprehensive understanding of synaptic plasticity and the molecular basis of learning and memory in a disease context can provide specific targets for the development of novel therapeutics targeting cognitive impairments in schizophrenia. Here, we describe the role of synaptic plasticity in cognition, summarize evidence for synaptic dysfunction in schizophrenia and demonstrate the use of patient derived induced-pluripotent stem cells for studying synaptic plasticity in vitro. Lastly, we discuss current advances and future technologies for bridging basic science research of synaptic dysfunction with clinical and translational research that can be used to predict treatment response and develop novel therapeutics.

Distinct effects of interleukin-6 and interferon-γ on differentiating human cortical neurons.

Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-γ. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-ß signaling while IFN-γ impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6, but not IFN-γ, altered mitochondrial respiration while IFN-γ, but not IL-6, induced reduction in dendritic spine density. Pre-treatment with folic acid, which has known neuroprotective and anti-inflammatory properties, ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest distinct mechanisms for how fetal IL-6 and IFN-γ exposure influence risk for neuropsychiatric disorders, and how folic acid can mitigate such risk.

Co-Culturing Microglia and Cortical Neurons Differentiated from Human Induced Pluripotent Stem Cells.

The ability to generate microglia from human induced pluripotent stem cells (iPSCs) provides new tools and avenues for investigating the role of microglia in health and disease. Furthermore, iPSC-derived microglia can be maintained in co-culture with iPSC-derived cortical neurons, which enable investigations of microglia-neuron interactions that are hypothesized to be dysregulated in a number of neuropsychiatric disorders. Human iPSCs were differentiated to generate microglia using an adapted version of a protocol developed by the Fossati group, and the iPSC-derived microglia were validated with marker analysis and real-time PCR. Human microglia generated using this protocol were positive for the markers CD11C, IBA1, P2RY12, and TMEM119, and expressed the microglial-related genes AIF1, CX3CR1, ITGAM, ITGAX, P2RY12, and TMEM119. Human iPSC-derived cortical neurons that had been differentiated for 30 days were plated with microglia and maintained in co-culture until day 60, when experiments were undertaken. The density of dendritic spines in cortical neurons in co-culture with microglia was quantified under baseline conditions and in the presence of pro-inflammatory cytokines. In order to examine how microglia modulate neuronal function, calcium imaging experiments of the cortical neurons were undertaken using the calcium indicator Fluo-4 AM. Live calcium activity of cortical neurons was obtained using a confocal microscope, and fluorescence intensity was quantified using ImageJ. This report describes how co-culturing human iPSC-derived microglia and cortical neurons provide new approaches to interrogate the effects of microglia on cortical neurons.

The Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo): Rationale, Methods, and Baseline Characteristics.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.

A systematic review of the association between biological markers and environmental stress risk factors for adolescent depression.

INTRODUCTION: Although the aetiology and pathophysiology of depression are multifactorial, to date most studies have examined either biological or environmental mechanisms without looking at the integration of both; with most studies conducted in high-income countries (HICs). Therefore, we conducted a systematic review of worldwide studies investigating the relationship between biological and environmental stress risk factors for major depressive disorder (MDD) in adolescence. METHODS: We searched MEDLINE (via Ovid), PsycINFO, Cochrane Database of Systematic Reviews, Web of Science (Core Collection), Lilacs, African Journals Online and Global Health for prospective and cross-sectional studies that examined the association between biological markers and environmental stress risk factors in MDD during adolescence. FINDINGS: Of 11,089 articles identified, 21 were included, with only two from middle-income countries. Increased inflammation, telomere length and brain abnormalities, including blunted reward-related activity, white matter disruptions, and altered volume of limbic brain regions, were associated with increased risk for MDD mainly in the context of early life adversity. There is little evidence suggesting that the neurobiological changes investigated were associated with MDD in the context of recent life stress. INTERPRETATION: The developmental trajectory of depression appears to start with early life adversities and occurs in the context of immune and brain abnormalities. Understanding these biopsychosocial processes will help to improve our ability to detect individuals at risk of developing depression in adolescence. However, generalizability is limited by few studies examining both biological and environmental stress risk factors and a lack of studies on adolescents and young adults in low-and-middle-income countries (LMICs).

Advances toward precision medicine for bipolar disorder: mechanisms & molecules.

Given its chronicity, contribution to disability and morbidity, and prevalence of more than 2%, the effective treatment, and prevention of bipolar disorder represents an area of significant unmet medical need. While more than half a century has passed since the introduction of lithium into widespread use at the birth of modern psychopharmacology, that medication remains a mainstay for the acute treatment and prevention of recurrent mania/hypomania and depression that characterize bipolar disorder. However, the continued limited understanding of how lithium modulates affective behavior and lack of validated cellular and animal models have resulted in obstacles to discovering more effective mood stabilizers with fewer adverse side effects. In particular, while there has been progress in developing new pharmacotherapy for mania, developing effective treatments for acute bipolar depression remain inadequate. Recent large-scale human genetic studies have confirmed the complex, polygenic nature of the risk architecture of bipolar disorder, and its overlap with other major neuropsychiatric disorders. Such discoveries have begun to shed light on the pathophysiology of bipolar disorder. Coupled with broader advances in human neurobiology, neuropharmacology, noninvasive neuromodulation, and clinical trial design, we can envision novel therapeutic strategies informed by defined molecular mechanisms and neural circuits and targeted to the root cause of the pathophysiology. Here, we review recent advances toward the goal of better treatments for bipolar disorder, and we outline major challenges for the field of translational neuroscience that necessitate continued focus on fundamental research and discovery.

Derivation, Expansion, Cryopreservation and Characterization of Brain Microvascular Endothelial Cells from Human Induced Pluripotent Stem Cells.

Brain microvascular endothelial cells (BMECs) can be differentiated from human induced pluripotent stem cells (iPSCs) to develop ex vivo cellular models for studying blood-brain barrier (BBB) function. This modified protocol provides detailed steps to derive, expand, and cryopreserve BMECs from human iPSCs using a different donor and reagents than those reported in previous protocols. iPSCs are treated with essential 6 medium for 4 days, followed by 2 days of human endothelial serum-free culture medium supplemented with basic fibroblast growth factor, retinoic acid, and B27 supplement. At day 6, cells are sub-cultured onto a collagen/fibronectin matrix for 2 days. Immunocytochemistry is performed at day 8 for BMEC marker analysis using CLDN5, OCLN, TJP1, PECAM1, and SLC2A1. Western blotting is performed to confirm BMEC marker expression, and absence of SOX17, an endodermal marker. Angiogenic potential is demonstrated with a sprouting assay. Trans-endothelial electrical resistance (TEER) is measured using chopstick electrodes and voltohmmeter starting at day 7. Efflux transporter activity for ATP binding cassette subfamily B member 1 and ATP binding cassette subfamily C member 1 is measured using a multi-plate reader at day 8. Successful derivation of BMECs is confirmed by the presence of relevant cell markers, low levels of SOX17, angiogenic potential, transporter activity, and TEER values ~2000 Ω x cm2. BMECs are expanded until day 10 before passaging onto freshly coated collagen/fibronectin plates or cryopreserved. This protocol demonstrates that iPSC-derived BMECs can be expanded and passaged at least once. However, lower TEER values and poorer localization of BMEC markers was observed after cryopreservation. BMECs can be utilized in co-culture experiments with other cell types (neurons, glia, pericytes), in three-dimensional brain models (organ-chip and hydrogel), for vascularization of brain organoids, and for studying BBB dysfunction in neuropsychiatric disorders.

Return to College After a First Episode of Psychosis.

A first episode of psychosis (FEP) can derail a patient's educational goals, including attainment of a college education, and this can have lasting ramifications for socioeconomic and health outcomes. Despite this, few studies have examined return to college, which is an important index of real-world educational success after a FEP. In this study, we conducted a longitudinal medical record review of patients in a transdiagnostic outpatient FEP program and performed survival analysis, setting return to college as the endpoint, among the subset of patients whose college education was interrupted. We found that 82% (93/114) of college-enrolled FEP individuals experienced disruptions to their education after FEP, but that return to college also occurred in a substantial proportion (49/88, 56%) among those on leave who had follow-up data. In this sample, the median time to college return was 18 months. When separated by baseline diagnostic category, FEP patients with affective psychotic disorders (FEAP, n = 45) showed faster time to college return than those with primary psychotic disorders (FEPP, n = 43) (median 12 vs 24 mo; P = .024, unadjusted). When adjusted for having no more than 1 psychiatric hospitalization at intake and absence of cannabis use in the 6 months prior to intake (which were also significant predictors), differences by diagnostic category were more significant (hazard ratio 2.66, 95% CI 1.43-4.94, P = .002). Participation in education is an important outcome for stakeholders, and students with FEP can be successful in accomplishing this goal.

Comparative Transcriptomic Analysis of Cerebral Organoids and Cortical Neuron Cultures Derived from Human Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (iPSCs) can be differentiated along various neuronal lineages to generate two-dimensional neuronal cultures as well as three-dimensional brain organoids. Such iPSC-derived cellular models are being utilized to study the basic biology of human neuronal function and to interrogate the molecular underpinnings of disease biology. The different cellular models generated from iPSCs have varying properties in terms of the diversity and organization of the cells as well as the cellular functions that are present. To understand transcriptomic differences in iPSC-derived monolayer neuronal cultures and three-dimensional brain organoids, we differentiated eight human iPSC lines from healthy control subjects to generate cerebral organoids and cortical neuron monolayer cultures from the same set of iPSC lines. We undertook RNA-seq experiments in these model systems and analyzed the gene expression data to identify genes that are differentially expressed in cerebral organoids and two-dimensional cortical neuron cultures. In cerebral organoids, gene ontology analysis showed enrichment of genes involved in tissue development, response to stimuli, and the interferon-γ pathway, while two-dimensional cortical neuron cultures showed enrichment of genes involved in nervous system development and neurogenesis. We also undertook comparative analysis of these gene expression profiles with transcriptomic data from the human fetal prefrontal cortex (PFC). This analysis showed greater overlap of the fetal PFC transcriptome with cerebral organoid gene expression profiles compared to monolayer cortical neuron culture profiles. Our studies delineate the transcriptomic differences between cortical neuron monolayer cultures and three-dimensional cerebral organoids and can help inform the appropriate use of these model systems to address specific scientific questions.

Mental Health Units in Correctional Facilities in the United States.

BACKGROUND: The prevalence of severe mental illness (SMI) in correctional settings is alarmingly high. Some correctional facilities have developed mental health units (MHUs) to treat incarcerated individuals with SMI. OBJECTIVE: To identify existing MHUs in the United States and collate information on these units. DATA SOURCES: A systematic review using Criminal Justice Abstracts, ERIC, PsycINFO, PubMed, and SocINDEX, plus an exploratory review using the Google search engine were conducted. MHUs were included if they were located within an adult correctional facility in the United States, specifically catered to SMI populations, and were in active operation as of June 2019. RESULTS: Eleven articles were identified through the peer-reviewed literature, but there were still major gaps in the information on MHUs. The Google search identified 317 MHUs. The majority of units were located within prisons (79.5%) and served only men (76%). The Google search found information indicating that 169 (53.3%) offered groups or programming to inmates; 104 (32.8%) offered individual therapy; and 89 (23%) offered both. One hundred sixty-six units (52.4%) had dedicated mental health staff, and 75 (23.7%) provided mental health training to correctional officers. Information on funding and outcomes of the MHUs is presented. LIMITATIONS: Use of the Google search engine and sources that have not been peer reviewed limits the robustness of conclusions about the MHUs. CONCLUSIONS: Standards for developing and implementing MHUs are not widespread. The shortcomings of current MHUs are discussed in the context of desired criteria for size, staffing, and programming.

Integrating stem cell-based experiments in clinical research.

With the seminal discovery of somatic cell reprogramming with defined genetic factors, it is now a routine laboratory procedure to reprogram somatic cells to generate patient-specific induced pluripotent stem cells (iPSCs) [1] Patient-specific iPSCs can be differentiated to generate mature neurons as well as three-dimensional brain organoids that show appropriate functional activity in electrophysiological studies [2,3]. However, there is a significant gap in the thoughtful incorporation of patient-derived neuronal cells in clinical studies addressing disease risk.

Transcriptome analysis and functional characterization of cerebral organoids in bipolar disorder.

BACKGROUND: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. METHODS: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. RESULTS: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER-mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. CONCLUSIONS: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission.

Transcriptomic Landscape and Functional Characterization of Induced Pluripotent Stem Cell-Derived Cerebral Organoids in Schizophrenia.

Importance: Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells (iPSCs) may be used to interrogate cellular-molecular underpinnings of schizophrenia. Objective: To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays. Design, Setting, and Participants: This case-control study was conducted at Massachusetts General Hospital between 2017 and 2019. Transcriptomic profiling of iPSC-derived cerebral organoids from 8 patients with schizophrenia and 8 healthy control individuals was undertaken to identify cellular pathways that are aberrant in schizophrenia. Induced pluripotent stem cells and cerebral organoids were generated from patients who had been diagnosed as having schizophrenia and from heathy control individuals. Main Outcomes and Measures: Transcriptomic analysis of iPSC-derived cerebral organoids from patients with schizophrenia show differences in expression of genes involved in synaptic biology and neurodevelopment and are enriched for genes implicated in schizophrenia genome-wide association studies (GWAS). Results: The study included iPSC lines generated from 11 male and 5 female white participants, with a mean age of 38.8 years. RNA sequencing data from iPSC-derived cerebral organoids in schizophrenia showed differential expression of genes involved in synapses, in nervous system development, and in antigen processing. The differentially expressed genes were enriched for genes implicated in schizophrenia, with 23% of GWAS genes showing differential expression in schizophrenia and control organoids: 10 GWAS genes were upregulated in schizophrenia organoids while 15 GWAS genes were downregulated. Analysis of the gene expression profiles suggested dysregulation of genes involved in mitochondrial function and those involved in modulation of excitatory and inhibitory pathways. Studies of mitochondrial respiration showed lower basal consumption rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption in schizophrenia cerebral organoids, without any differences in the extracellular acidification rate. Microelectrode array studies of cerebral organoids showed no differences in baseline electrical activity in schizophrenia but revealed a diminished response to stimulation and depolarization. Conclusions and Relevance: Investigations of patient-derived cerebral organoids in schizophrenia revealed gene expression patterns suggesting dysregulation of a number of pathways in schizophrenia, delineated differences in mitochondrial function, and showed deficits in response to stimulation and depolarization in schizophrenia.

Two-year diagnostic stability in a real-world sample of individuals with early psychosis.

OBJECTIVES: Diagnostic shifts in first episode psychosis (FEP) are not uncommon. Many studies examining diagnostic stability use structured diagnostic interviews. Less is known about the stability of FEP diagnoses made clinically. METHODS: We conducted a retrospective chart review of patients enrolled in a transdiagnostic FEP clinic. For the 96 patients followed clinically at least 2 years, we compared diagnoses at intake and 24 months. RESULTS: Diagnostic stability was high for bipolar disorder (89%), schizoaffective disorder (89%), and schizophrenia (82%). Psychosis not otherwise specified (13%) was more unstable, with limited baseline differences that would enable clinicians to predict who would convert to a primary psychotic vs affective psychotic disorder. CONCLUSIONS: Our real-world clinical sample shows that FEP diagnoses, with the exception of unspecified psychosis, are diagnostically stable, even without structured diagnostic interviews.

The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia.

BACKGROUND: Despite decades of research, little clarity exists regarding pathogenic mechanisms related to schizophrenia. Investigations on the disease biology of schizophrenia have primarily focused on neuronal alterations. However, there is substantial evidence pointing to a significant role for the brain's microvasculature in mediating neuroinflammation in schizophrenia. SUMMARY: Brain microvascular endothelial cells (BMEC) are a central element of the microvasculature that forms the blood-brain barrier (BBB) and shields the brain against toxins and immune cells via paracellular, transcellular, transporter, and extracellular matrix proteins. While evidence for BBB dysfunction exists in brain disorders, including schizophrenia, it is not known if BMEC themselves are functionally compromised and lead to BBB dysfunction. KEY MESSAGES: Genome-wide association studies, postmortem investigations, and gene expression analyses have provided some insights into the role of the BBB in schizophrenia pathophysiology. However, there is a significant gap in our understanding of the role that BMEC play in BBB dysfunction. Recent advances differentiating human BMEC from induced pluripotent stem cells (iPSC) provide new avenues to examine the role of BMEC in BBB dysfunction in schizophrenia.