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Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Research in the field of traumatic brain injury has until now heavily relied on the use of animal models to identify potential therapeutic approaches. However, a long series of failed clinical trials has brought many scientists to question the translational reliability of pre-clinical results obtained in animals. The search for an alternative to conventional models that better replicate human pathology in traumatic brain injury is thus of the utmost importance for the field. Recently, orthotopic xenotransplantation of human brain organoids into living animal models has been achieved. This review summarizes the existing literature on this new method, focusing on its potential applications in preclinical research, both in the context of cell replacement therapy and disease modelling. Given the obvious advantages of this approach to study human pathologies in an in vivo context, we here critically review its current limitations while considering its possible applications in traumatic brain injury research., (© 2024. The Author(s).)

Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis., (© 2024. The Author(s).)

Importance: Cognitive impairment contributes significantly to clinical outcome and level of function in individuals with psychotic disorders. These impairments are present already at psychosis onset at a group level; however, the question of heterogeneity in cognitive function among patients has not been systematically investigated., Objective: To provide an updated quantification of cognitive impairment at psychosis onset before patients receive potentially confounding antipsychotic treatment, and to investigate variability in cognitive function compared with healthy controls., Data Sources: In this systematic review and meta-analysis, PubMed articles were searched up to September 15, 2022., Study Selection: Original studies reporting data on cognitive function in antipsychotic drug-naive patients with first-episode psychosis (FEP) were included., Data Extraction and Synthesis: Data were independently extracted by 2 researchers. Cognitive tasks were clustered according to 6 domains of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery and the domain of executive function. Random-effects model meta-analyses of mean differences and coefficient of variation ratios (CVRs) were performed, as well as meta-regressions, assessment of study quality, and publication bias., Main Outcomes and Measures: The main outcome measure was Hedges g for mean differences in cognition and CVR for within-group variability., Results: Fifty studies were included in the analysis with a total of 2625 individuals with FEP (mean [SD] age, 25.2 [3.6] years, 60% male; 40% female) and 2917 healthy controls (mean [SD] age, 26.0 [4.6]; 55% male; 45% female). In all cognitive domains, the FEP group displayed significant impairment compared with controls (speed of processing: Hedges g = -1.16; 95% CI, -1.35 to -0.98; verbal learning: Hedges g = -1.08; 95% CI, -1.28 to -0.88; visual learning: Hedges g = -1.05; 95% CI, -1.27 to -0.82; working memory: Hedges g = -1.04; 95% CI, -1.35 to -0.73; attention: Hedges g = -1.03; 95% CI, -1.24 to -0.82; reasoning/problem solving: Hedges g = -0.90; 95% CI, -1.12 to -0.68; executive function: Hedges g = -0.88; 95% CI, -1.07 to -0.69). Individuals with FEP also exhibited a larger variability across all domains (CVR range, 1.34-1.92)., Conclusions and Relevance: Results of this systematic review and meta-analysis identified cognitive impairment in FEP before the initiation of antipsychotic treatment, with large effect sizes. The high variability within the FEP group suggests the need to identify those individuals with more severe cognitive problems who risk worse outcomes and could benefit the most from cognitive remediation.

Apart from their diagnostic, monitoring, or prognostic utility in clinical settings, molecular biomarkers may be instrumental in understanding the pathophysiology of psychiatric disorders, including schizophrenia. Using untargeted metabolomics, we recently identified eight cerebrospinal fluid (CSF) metabolites unique to first-episode psychosis (FEP) subjects compared to healthy controls (HC). In this study, we sought to investigate the CSF proteomic signatures associated with FEP. We employed 16-plex tandem mass tag (TMT) mass spectrometry (MS) to examine the relative protein abundance in CSF samples of 15 individuals diagnosed with FEP and 15 age-and-sex-matched healthy controls (HC). Multiple linear regression model (MLRM) identified 16 differentially abundant CSF proteins between FEP and HC at p < 0.01. Among them, the two most significant CSF proteins were collagen alpha-2 (IV) chain (COL4A2: standard mean difference [SMD] = -1.12, p = 1.64 × 10 -4 ) and neuron-derived neurotrophic factor (NDNF: SMD = -1.03, p = 4.52 × 10 -4 ) both of which were down-regulated in FEP subjects compared to HC. We also identified several potential CSF proteins associated with the pathophysiology and the symptom profile and severity in FEP subjects, including COL4A2, NDNF, hornerin (HRNR), contactin-6 (CNTN6), voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3), tropomyosin alpha-3 chain (TPM3 and TPM4). Moreover, several protein signatures were associated with cognitive performance. Although the results need replication, our exploratory study suggests that CSF protein signatures can be used to increase the understanding of the pathophysiology of psychosis., Competing Interests: Declaration of competing interest All authors declare that the research was conducted without commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10 -05 ), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Hypothesis: Immune activation is suggested to play an important role in psychosis. In this study, a large number of immune-related proteins were analyzed to obtain a more comprehensive picture of immune aberrations in schizophrenia., Study Design: Ninety-two immune markers were analyzed by the Olink Protein Extension Assay (Inflammatory Panel) in plasma and cerebrospinal fluid (CSF) from 77 first-episode psychosis (FEP) patients (of which 43 later received the diagnosis of schizophrenia) and 56 healthy controls, all recruited from the Karolinska Schizophrenia Project (KaSP), Stockholm, Sweden., Study Results: Differential analysis showed that 12 of 92 inflammatory proteins were significantly higher in the plasma of FEP patients (n = 77) than in controls, and several proteins were positively correlated with disease severity. Patients from the same cohort diagnosed with schizophrenia (n = 43), showed significantly higher levels of 15 plasma proteins compared to controls whereas those not receiving this diagnosis showed no significant differences. The presently used OLINK inflammatory panel allowed the detection of only 47 CSF proteins of which only CD5 differed between patients and controls., Conclusions: The levels of several peripheral immune markers, particularly those interfering with WNT/β-catenin signaling, were significantly higher in patients with FEP than in healthy controls and associated with illness severity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects., Methods: Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay., Results: CSF dopamine was reliably detected in 50 % of healthy controls and in 65 % of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning., Conclusions: Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard., Competing Interests: Declaration of competing interest All authors declare they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Neurodevelopmental disorders arise due to various risk factors that can perturb different stages of brain development, and a combinatorial impact of these risk factors programs the phenotype in adulthood. While modeling the complete phenotype of a neurodevelopmental disorder is challenging, individual developmental perturbations can be successfully modeled in vivo in animals and in vitro in human cellular models. Nevertheless, our limited knowledge of human brain development restricts modeling strategies and has raised questions of how well a model corresponds to human in vivo brain development. Recent progress in high-resolution analysis of human tissue with single-cell and spatial omics techniques has enhanced our understanding of the complex events that govern the development of the human brain in health and disease. This new knowledge can be utilized to improve modeling of neurodevelopmental disorders and pave the way to more accurately portraying the relevant developmental perturbations in disease models., (© 2022. The Author(s).)

Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology., (© 2022. The Author(s).)

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19., (© 2022. The Author(s).)

Introduction: Social dysfunction is a key feature of psychotic disorders such as schizophrenia linked to disability. Less is known about social functioning in the early stages of the disorder and if there is an association to psychotic symptoms., Aims: Investigate if antipsychotic drug-naïve or briefly medicated individuals with first-episode psychosis (FEP), have impaired facial affect recognition (FAR) compared to control participants and if psychotic symptoms are associated with the FAR ability., Method: Individuals with FEP (n = 67) and control participants (n = 51) performed a computer-aided FAR task on basic emotions. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Group performances were compared using age and gender as covariates. The associations between FAR and performance on the subscales of PANSS were analyzed., Results: Compared to control participants, individuals with FEP were impaired in general FAR (Beta = -2.04 [95 % conf: -3.75/-1.62], p < 0.001) and FAR of negative emotions (Beta = -1.74 [95 % conf: -3.08/-1.22], p < 0.001), driven by difficulties in recognition of anger and disgust. In both groups, there was a pattern of mistaking negative emotions for other negative emotions. There were no significant group differences in FAR of happiness. No significant associations between FAR and psychotic symptoms were observed., Discussion: The results indicate that FAR, an underlying mechanism of social functioning is impaired early in the course of psychotic disorders. Current findings do not support the hypothesis that misinterpretation of facial expressions in individuals with FEP underlies or contributes to symptoms of psychosis., Competing Interests: The authors declare the following conflict of interests: Sven Bölte was an author, consultant, or lecturer for Medice and Roche during the last 3 years. He receives royalties for textbooks and diagnostic tools from Hogrefe Publishers and is a shareholder in SB Education and Psychological Consulting and NeuroSupportSolutions International. Carl M. Sellgren is a scientific advisor to Outermost Therapeutics Inc., (© 2022 The Author(s).)

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A 2A R), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A 2A R with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A 2A R crosstalk may regulate dopamine function in a therapeutically targetable manner., (© 2022. The Author(s).)

Psychotic disorders are currently diagnosed by examining the patient's mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers., (© 2022. The Author(s).)

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [ 11 C]FLB457. The main outcome was D2-R binding potential (BP ND ) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BP ND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity., (© 2021. The Author(s).)

Background: Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent mood episodes interspersed with euthymic periods. A growing number of studies have indicated that zinc plays an important role in coordinating immune responses, as well as being involved in synaptic transmission. In the current study, we set out to measure serum levels of zinc in a meticulously phenotyped cohort of 121 euthymic BD subjects and 30 matched controls., Methods: Serum levels of zinc were measured by photometry. To assess the interplay between zinc levels and immune activation in BD, we measured serum levels of high-sensitive C-reactive protein (hsCRP) levels by immunoturbidimetric assay, and serum levels of monocyte chemoattractant protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble cluster of differentiation 14 (sCD14) by electrochemiluminescence enzyme-linked immunosorbent assays. The baseline clinical diagnostic instrument for BD was the Affective Disorder Evaluation, and executive functioning was assessed by using the Delis-Kaplan Executive Function System., Results: Controlling for potential confounding factors, BD patients displayed increased serum levels of zinc unrelated to hsCRP, MCP-1, YKL-40, and sCD14 levels. Serum levels of zinc did not associate with executive functioning or measurements of disease severity., Discussion: This study suggests that the zinc homeostasis is disturbed in BD and that this dyshomeostasis is not related to ongoing mood symptoms or immune activation. Of note, serum levels were increased and hence do not support continuous zinc supplementation in BD., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The number of successful drug development projects has been stagnant for decades despite major breakthroughs in chemistry, molecular biology, and genetics. Unreliable target identification and poor translatability of preclinical models have been identified as major causes of failure. To improve predictions of clinical efficacy and safety, interest has shifted to three-dimensional culture methods in which human cells can retain many physiologically and functionally relevant phenotypes for extended periods of time. Here, we review the state of the art of available organotypic culture techniques and critically review emerging models of human tissues with key importance for pharmacokinetics, pharmacodynamics, and toxicity. In addition, developments in bioprinting and microfluidic multiorgan cultures to emulate systemic drug disposition are summarized. We close by highlighting important trends regarding the fabrication of organotypic culture platforms and the choice of platform material to limit drug absorption and polymer leaching while supporting the phenotypic maintenance of cultured cells and allowing for scalable device fabrication. We conclude that organotypic and microphysiological human tissue models constitute promising systems to promote drug discovery and development by facilitating drug target identification and improving the preclinical evaluation of drug toxicity and pharmacokinetics. There is, however, a critical need for further validation, benchmarking, and consolidation efforts ideally conducted in intersectoral multicenter settings to accelerate acceptance of these novel models as reliable tools for translational pharmacology and toxicology. SIGNIFICANCE STATEMENT: Organotypic and microphysiological culture of human cells has emerged as a promising tool for preclinical drug discovery and development that might be able to narrow the translation gap. This review discusses recent technological and methodological advancements and the use of these systems for hit discovery and the evaluation of toxicity, clearance, and absorption of lead compounds., (Copyright © 2022 The Author(s).)

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-D-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these-and other-limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher's test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients., (© 2021. The Author(s).)

The G protein-coupled receptor kinase (GRK) family member protein GRK3 has been linked to the pathophysiology of schizophrenia and bipolar disorder. Expression, as well as protein levels, of GRK3 are reduced in post-mortem prefrontal cortex of schizophrenia subjects. Here, we investigate functional behavior and neurotransmission related to immune activation and psychosis using mice lacking functional Grk3 and utilizing a variety of methods, including behavioral, biochemical, electrophysiological, molecular, and imaging methods. Compared to wildtype controls, the Grk3 -/- mice show a number of aberrations linked to psychosis, including elevated brain levels of IL-1β, increased turnover of kynurenic acid (KYNA), hyper-responsiveness to D-amphetamine, elevated spontaneous firing of midbrain dopamine neurons, and disruption in prepulse inhibition. Analyzing human genetic data, we observe a link between psychotic features in bipolar disorder, decreased GRK expression, and increased concentration of CSF KYNA. Taken together, our data suggest that Grk3 -/- mice show face and construct validity relating to the psychosis phenotype with glial activation and would be suitable for translational studies of novel immunomodulatory agents in psychotic disorders., (© 2021. The Author(s).)

Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [ 11 C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (β = 0.013-0.074, partial r = -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BF H0:H1  = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations., (© 2021. The Author(s).)

Background: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders., Methods: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics., Results: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network., Limitations: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined., Conclusion: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging-genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder., Competing Interests: Dr. Landén reports grants from the Swedish Medical Research Council, the Swedish Foundation for Strategic Research and the Swedish Federal Government during the conduct of the study. No other competing interests declared., (© 2021 CMA Joule Inc. or its licensors.)

Background: Cross-sectional studies have found impaired cognitive functioning in patients with bipolar disorder, but long-term longitudinal studies are scarce., Aims: The aims of this study were to examine the 6-year longitudinal course of cognitive functioning in patients with bipolar disorder and healthy controls. Subsets of patients were examined to investigate possible differences in cognitive trajectories., Method: Patients with bipolar I disorder (n = 44) or bipolar II disorder (n = 28) and healthy controls (n = 59) were tested with a comprehensive cognitive test battery at baseline and retested after 6 years. We conducted repeated measures ANCOVAs with group as a between-subject factor and tested the significance of group and time interaction., Results: By and large, the change in cognitive functioning between baseline and follow-up did not differ significantly between participants with bipolar disorder and healthy controls. Comparing subsets of patients, for example those with bipolar I and II disorder and those with and without manic episodes during follow-up, did not reveal subgroups more vulnerable to cognitive decline., Conclusions: Cognitive performance remained stable in patients with bipolar disorder over a 6-year period and evolved similarly to healthy controls. These findings argue against the notion of a general progressive decline in cognitive functioning in bipolar disorder.

Schizophrenia is a severe mental disorder and one of its characteristics is cognitive impairments. Findings regarding levels of the heme metabolite and plasma antioxidant bilirubin in schizophrenia are inconclusive. However, a recently published study indicate that low levels of bilirubin may be implicated in the memory impairments seen in the disorder. The aim of this cross-sectional study was to investigate the levels of bilirubin in individuals with a first-episode psychosis (FEP) and to examine if bilirubin levels were associated to cognitive impairments, symptoms and duration of untreated psychosis (DUP). Bilirubin levels were reduced in 39 individuals with FEP compared with 20 HC (median [IQR]: 11.0 [9.0-13.0] µM vs. 15.0 [11.5-18.5] µM). In individuals with FEP, bilirubin levels were also positively correlated to two working memory tests (r = 0.40 and r = 0.32) and inversely correlated to DUP (r = - 0.36). Findings were not influenced by confounding factors. The results confirm the antioxidant deficit previously seen in schizophrenia, but also indicate that these changes may be related to DUP. The study also confirms that bilirubin may be implicated in the cognitive deficits that accompanies the disorder, here for the first time presented in individuals with FEP.

Microglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo. We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.

The kynurenine pathway of tryptophan degradation produces several neuroactive metabolites such as kynurenic acid (KYNA), quinolinic acid (QUIN), and picolinic acid (PIC) thought to be involved in the pathophysiology of psychosis, major depression, and suicidal behavior. Here, we analyzed cerebrospinal fluid (CSF) concentrations of tryptophan, kynurenine, KYNA, QUIN, and PIC utilizing ultra-performance liquid chromatography - tandem mass spectrometry system (UPLC-MS/MS) in persons with bipolar disorder (n = 101) and healthy controls (n = 80) to investigate if the metabolites correlated with depressive symptoms or to the history of suicidal behavior. Furthermore, we analyzed if genetic variants of the enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) were associated with the CSF concentrations of PIC and QUIN. We found that CSF KYNA and PIC concentrations, as well as the kynurenine/tryptophan ratio were increased in bipolar disorder compared with controls. CSF PIC concentrations were lower in subjects with a history of suicidal behavior than those without, supporting the hypothesis that low CSF PIC is a marker of vulnerability for suicidality. Bipolar subjects taking antidepressants had higher CSF concentrations of kynurenine and KYNA than subjects not given these medications. A negative association was found between a genetic variant of ACMSD and the ratio of PIC/QUIN, indicating that a polymorphism in ACMSD is associated with excess of QUIN formation at the expense of PIC. The present results confirm that the kynurenine pathway is activated in bipolar disorder, and suggest that shifting the activity of the kynurenine pathway away from QUIN production towards a production of KYNA and PIC might be a beneficial therapeutic strategy., Competing Interests: Declaration of Competing Interest C.M.S. is a scientific adviser for Outermost Therapeutics (of no relevance to this work). S.E. discloses grant support from AstraZeneca and Jansen Pharmaceuticals as principal investigator and has been a speaker for Roche Pharmaceuticals, AstraZeneca, Eli Lilly, Orion Corporation Orion Pharma and Bristol Myers Squibb (none of these are relevant to this work). The remaining authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Bipolar disorder is a severe psychiatric disorder which affects more than 1% of the world's population and is a leading cause of disability among young people. For the past 50 years, lithium has been the drug of choice for maintenance treatment of bipolar disorder due to its potent ability to prevent both manic and depressive episodes as well as suicide. However, though lithium has been associated with a multitude of effects within different cellular pathways and biological systems, its specific mechanism of action in stabilizing mood remains largely elusive. Mitochondrial dysfunction and telomere shortening have been implicated in both the pathophysiology of bipolar disorder and as targets of lithium treatment. Interestingly, it has in recent years become clear that these phenomena are intimately linked, partly through reactive oxygen species signaling and the subcellular translocation and non-canonical actions of telomerase reverse transcriptase. In this review, we integrate the current understanding of mitochondrial dysfunction, oxidative stress and telomere shortening in bipolar disorder with documented effects of lithium. Moreover, we propose that lithium's mechanism of action is intimately connected with the interdependent regulation of mitochondrial bioenergetics and telomere maintenance., (Copyright © 2020 Lundberg, Millischer, Backlund, Martinsson, Stenvinkel, Sellgren, Lavebratt and Schalling.)

Objective: To investigate external factors that trigger manic and hypomanic relapses and how this is associated with personality and clinical outcome measured as number of affective episodes over a 7-year period., Method: This is a prospective cohort study of 204 meticulously characterized Swedish bipolar disorder patients. Personality was evaluated at baseline using the Swedish universities Scales of Personality in 170 patients, and 90 patients were followed up after approximately 7 years in order to evaluate clinical outcomes., Results: We found that 44% of the patients reported trigger factors, including sleep disturbance, work- or family-related issues, medication, and illicit drug use. There were no significant differences in any of the personality traits when comparing the 74 patients that reported triggers with the 90 patients that did not. At 7-year follow-up, there was no difference between the groups in number of affective episodes (depressive, hypomanic, manic, or mixed), involuntary commitments, suicide attempts, or self-harm incidents since baseline., Conclusions: Around 40% of the patients reported external triggers for manic and hypomanic episodes. However, this was neither associated with personality traits nor number of affective episodes at 7-year follow-up., (© 2020 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Post-mortem studies consistently show evidence of reduced synaptic protein levels in patients with schizophrenia. Clinically high-risk subjects show a steeper decrease in grey matter thickness and in vitro modeling using patient-derived cells implicate excessive synaptic pruning during neurodevelopment as a part of the schizophrenia pathophysiology. However, it is unclear to what extent synapse elimination is present during various stages of the disease, which is of clinical importance as in a real-world setting most subjects received their first-episode psychosis (FEP) diagnosis not until their mid-twenties. In the present study, we measured cerebrospinal fluid (CSF) concentrations of the two pre-synaptic proteins synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1), both of which are increased in conditions of ongoing synaptic degeneration, in 44 FEP subjects (mean age 29.9 years) and 21 healthy controls (25.9 years) using immunoprecipitation mass spectrometry. Neither protein was found to differ between healthy controls and patients, and they showed no correlation with symptom ratings, cognitive performance or antipsychotic medication. Additional studies in high-risk subjects in the early prodromal phase will be needed to address if excessive synapse destruction occurs before the development of overt psychotic symptoms., Competing Interests: Sophie Erhardt has received grant support from AstraZeneca and Jansen Pharmaceuticals as principal investigator and has been a speaker for Roche Pharmaceuticals, Astra Zeneca, Eli Lilly and Bristol Myers Squibb. Carl Sellgren is a co-founder of Outermost Therapeutics Inc. HZ has served at scientific advisory boards of Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. KB has served as a consultant or at advisory boards for Alector, Alzheon, CogRx, Biogen, Lilly, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. There are no commercial associations that might pose a conflict of interest in connection with the manuscript. No funding sources had any role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. None of the other authors declare any competing interests., (© 2020 The Author(s).)

The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

Bipolar disorder is a common, chronic psychiatric disorder. Despite high heritability, there is a paucity of identified genetic risk factors. Immune biomarkers are under more direct genetic influence than bipolar disorder. To explore the genetic associations with immune biomarker levels in cerebrospinal fluid (CSF) and blood serum which previously showed differences in bipolar disorder, we performed a study involving 291 individuals (184 bipolar disorder patients and 107 controls). The biomarkers assayed in both CSF and serum were: chitinase-3-like protein-1 (YKL-40), monocyte chemoattractant protein-1 (MCP-1), soluble cluster of differentiation (sCD14), tissue inhibitor of metalloproteinases-1 and 2 (TIMP-1 and TIMP-2). C-reactive protein (CRP) was only quantified in serum, and interleukin 8 (IL-8) measures were only available in CSF. Genome-wide association studies were conducted using PLINK for each of three genotyping waves and incorporated covariates for population substructure, age, sex, and body mass index (BMI). Results were combined by meta-analysis. Genome-wide significant associations were detected for all biomarkers except TIMP-1 and TIMP-2 in CSF. The strongest association in CSF was found for markers within the CNTNAP5 gene with YKL-40 (rs150248456, P = 2.84 × 10 -10 ). The strongest association in serum was also for YKL-40 but localized to the FANCI gene (rs188263039, P = 5.80 × 10 -26 ). This study revealed numerous biologically plausible genetic associations with immune biomarkers in CSF and blood serum. Importantly, the genetic variants regulating immune biomarker levels in CSF and blood serum differ. These results extend our knowledge of how biomarkers showing alterations in bipolar disorder are genetically regulated.

Background: Bipolar disorder (BD) is a highly heritable psychiatric disorder characterized by episodes of manic and depressed mood states and associated with cortical brain abnormalities. Although the course of BD is often progressive, longitudinal brain imaging studies are scarce. It remains unknown whether brain abnormalities are static traits of BD or result from pathological changes over time. Moreover, the genetic effect on implicated brain regions remains unknown., Methods: Patients with BD and healthy control (HC) subjects underwent structural magnetic resonance imaging at baseline (123 patients, 83 HC subjects) and after 6 years (90 patients, 61 HC subjects). Cortical thickness maps were generated using FreeSurfer. Using linear mixed effects models, we compared longitudinal changes in cortical thickness between patients with BD and HC subjects across the whole brain. We related our findings to genetic risk for BD and tested for effects of demographic and clinical variables., Results: Patients showed abnormal cortical thinning of temporal cortices and thickness increases in visual/somatosensory brain areas. Thickness increases were related to genetic risk and lithium use. Patients who experienced hypomanic or manic episodes between time points showed abnormal thinning in inferior frontal cortices. Cortical changes did not differ between diagnostic BD subtypes I and II., Conclusions: In the largest longitudinal BD study to date, we detected abnormal cortical changes with high anatomical resolution. We delineated regional effects of clinical symptoms, genetic factors, and medication that may explain progressive brain changes in BD. Our study yields important insights into disease mechanisms and suggests that neuroprogression plays a role in BD., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.

Metabolites of the kynurenine pathway of tryptophan degradation, in particular, the N-Methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA), are increasingly recognized as primary pathophysiological promoters in several psychiatric diseases. Studies analyzing central KYNA levels from subjects with psychotic disorders have reported increased levels. However, sample sizes are limited and in contrast many larger studies examining this compound in blood from psychotic patients commonly report a decrease. A major question is to what extent peripheral KYNA levels reflect brain KYNA levels under physiological as well as pathophysiological conditions. Here we measured KYNA in plasma from a total of 277 subjects with detailed phenotypic data, including 163 BD subjects and 114 matched healthy controls (HCs), using an HPLC system. Among them, 94 BD subjects and 113 HCs also had CSF KYNA concentrations analyzed. We observe a selective increase of CSF KYNA in BD subjects with previous psychotic episodes although this group did not display altered plasma KYNA levels. In contrast, BD subjects with ongoing depressive symptoms displayed a tendency to decreased plasma KYNA concentrations but unchanged CSF KYNA levels. Sex and age displayed specific effects on KYNA concentrations depending on if measured centrally or in the periphery. These findings implicate brain-specific regulation of KYNA under physiological as well as under pathophysiological conditions and strengthen our previous observation of CSF KYNA as a biomarker in BD. In summary, biomarker and drug discovery studies should include central KYNA measurements for a more reliable estimation of brain KYNA levels.

Objective: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein-1 (MCP-1) and chitinase-3-like protein 1 (YKL-40) were investigated in plasma and cerebrospinal fluid (CSF) in first-episode psychosis (FEP) patients., Method: CSF and blood were sampled from 42 first-episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL-40 and MCP-1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN-9000-hematology analyzer., Results: We found higher plasma levels of MCP-1 and YKL-40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL-40 levels in the CSF of tobacco-free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning., Conclusion: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL-40 and MCP-1 in the initiation and progression of schizophrenia., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.

Previous studies on the relationship between autoimmune diseases, schizophrenia, and bipolar disorder are mainly based on hospital discharge registers with insufficient coverage of outpatient data. Furthermore, data is scant on the prevalence of autoimmune diseases in bipolar subgroups. Here we estimate the self-reported prevalences of autoimmune diseases in schizophrenia, bipolar disorder type I and II, and controls. Lifetime prevalence of autoimmune diseases was assessed through a structured interview in a sample of 9076 patients (schizophrenia N = 5278, bipolar disorder type I N = 1952, type II N = 1846) and 6485 controls. Comparative analyses were performed using logistic regressions. The prevalence of diabetes type 1 did not differ between groups. Hyperthyroidism, hypothyroidism regardless of lithium effects, rheumatoid arthritis, and polymyalgia rheumatica were most common in bipolar disorder. Systemic lupus erythematosus was less common in bipolar disorder than in the other groups. The rate of autoimmune diseases did not differ significantly between bipolar subgroups. We conclude that prevalences of autoimmune diseases show clear differences between schizophrenia and bipolar disorder, but not between the bipolar subgroups., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To understand the etiology of cognitive impairment associated with bipolar disorder, we need to clarify potential heterogeneity in cognitive functioning. To this end, we used multivariate techniques to study if the correlation structure of cognitive abilities differs between persons with bipolar disorder and controls., Method: Clinically stable patients with bipolar disorder (type I: n = 64; type II: n = 44) and healthy controls (n = 86) were assessed with a wide range of cognitive tests measuring executive function, speed, memory, and verbal skills. Data were analysed with multivariate techniques., Results: A distinct subgroup (∼30%) could be identified that performed significantly poorer on tests concerning memory function. This cognitive phenotype subgroup did not differ from the majority of bipolar disorder patients with respect to other demographic or clinical characteristics., Conclusions: Whereas the majority of patients performed similar to controls, a subgroup of patients with bipolar disorder differed substantially from healthy controls in the correlation pattern of low-level cognitive abilities. This suggests that cognitive impairment is not a general trait in bipolar disorder but characteristic of a cognitive subgroup. This has important clinical implications for cognitive rehabilitation and remediation.

Background: One-fourth of children with cerebral malaria (CM) retain cognitive sequelae up to 2 years after acute disease. The kynurenine pathway of the brain, forming neuroactive metabolites, e.g. the NMDA-receptor antagonist kynurenic acid (KYNA), has been implicated in long-term cognitive dysfunction in other CNS infections. In the present study, the association between the kynurenine pathway and neurologic/cognitive complications in children with CM was investigated., Methods: Cerebrospinal fluid (CSF) concentrations of KYNA and its precursor kynurenine in 69 Ugandan children admitted for CM to Mulago Hospital, Kampala, Uganda, between 2008 and 2013 were assessed. CSF kynurenine and KYNA were compared to CSF cytokine levels, acute and long-term neurologic complications, and long-term cognitive impairments. CSF kynurenine and KYNA from eight Swedish children without neurological or infectious disease admitted to Astrid Lindgren's Children's Hospital were quantified and used for comparison., Results: Children with CM had significantly higher CSF concentration of kynurenine and KYNA than Swedish children (P < 0.0001 for both), and CSF kynurenine and KYNA were positively correlated. In children with CM, CSF kynurenine and KYNA concentrations were associated with coma duration in children of all ages (P = 0.003 and 0.04, respectively), and CSF kynurenine concentrations were associated with worse overall cognition (P = 0.056) and attention (P = 0.003) at 12-month follow-up in children ≥5 years old., Conclusions: CSF KYNA and kynurenine are elevated in children with CM, indicating an inhibition of glutamatergic and cholinergic signaling. This inhibition may lead acutely to prolonged coma and long-term to impairment of attention and cognition.

Background: Anxiety disorders are highly prevalent in people with bipolar disorder, but it is not clear how many have anxiety disorders even at times when they are free of major mood episodes. We aimed to establish what proportion of euthymic individuals with bipolar disorder meet diagnostic criteria for anxiety disorders., Method: We performed a random-effects meta-analysis of prevalence rates of current DSM-III- and DSM-IV-defined anxiety disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder, specific phobia, obsessive-compulsive disorder, post-traumatic stress disorder, and anxiety disorder not otherwise specified) in euthymic adults with bipolar disorder in studies published by 31 December 2015., Results: Across 10 samples with 2120 individuals with bipolar disorder, 34.7% met diagnostic criteria for one or more anxiety disorders during euthymia [95% confidence interval (CI) 23.9-45.5%]. Direct comparison of 189 euthymic individuals with bipolar disorder and 17 109 population controls across three studies showed a 4.6-fold increase (risk ratio 4.60, 95% CI 2.37-8.92, p < 0.001) in prevalence of anxiety disorders in those with bipolar disorder., Conclusions: These findings suggest that anxiety disorders are common in people with bipolar disorder even when their mood is adequately controlled. Euthymic people with bipolar disorder should be routinely assessed for anxiety disorders and anxiety-focused treatment should be initiated if indicated.

Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening., Competing Interests: CMS discloses lecture and consulting fees from Otsuka Pharmaceutical and H Lundbeck A/S (none of these are relevant to this work). RHP has served on scientific advisory boards or consulted to Genomind, Perfect Health, Psybrain, and RID Ventures (none of these are relevant to this work). The remaining authors declare no conflicts of interest.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder., Competing Interests: The authors declare no conflict of interest.