Endophenotype Of Schizophrenia Research Articles

Bistable Perception Discriminates Between Depressive Patients, Controls, Schizophrenia Patients, and Their Siblings.

Individuals with schizophrenia have less priors than controls, meaning they rely less upon their prior experiences to interpret the current stimuli. These differences in priors are expected to show as higher alternation rates in bistable perception tasks like the Structure-from-Motion (SfM) paradigm. In this paradigm, continuously moving dots in two dimensions are perceived subjectively as traveling along a three-dimensional sphere, which results in a direction of motion (left or right) that shifts approximately every few seconds. Here, we tested healthy controls, patients with schizophrenia, siblings of patients with schizophrenia, and patients with depression with both the intermittent and continuous variants of the SfM paradigm. In the intermittent variant of the SfM paradigm, depressive patients exhibited the lowest alternation rate, followed by unaffected controls. In contrast, patients with schizophrenia and their unaffected siblings displayed significantly higher alternation rates. In the continuous variant of the SfM paradigm, patients with schizophrenia showed the lowest mean percept durations, while there were no differences between the other three groups. The intermittent SfM paradigm is a candidate endophenotype for schizophrenia. The aberrant processing in the patients may stem from alterations in adaptation and/or cross-inhibition mechanisms leading to changes in priors, as suggested by current models in the field. The intermittent SfM paradigm is, hence, a trait marker that offers the great opportunity to investigate perceptual abnormalities across the psychiatry spectrum, ranging from depression to psychosis.

Analyzing language ability in first-episode psychosis and their unaffected siblings: A diffusion tensor imaging tract-based spatial statistics analysis study

Schizophrenia (SZ) is a highly heritable mental disorder, and language dysfunctions play a crucial role in diagnosing it. Although language-related symptoms such as disorganized speech were predicted by the polygenic risk for SZ which emphasized the common genetic liability for the disease, few studies investigated possible white matter integrity abnormalities in the language-related tracts in those at familial high-risk for SZ. Also, their results are not consistent. In this current study, we examined possible aberrations in language-related white matter tracts in patients with first-episode psychosis (FEP, N = 20), their siblings (SIB, N = 20), and healthy controls (CON, N = 20) by applying whole-brain Tract-Based Spatial Statistics and region-of-interest analyses. We also assessed language ability by Thought and Language Index (TLI) using Thematic Apperception Test (TAT) pictures and verbal fluency to see whether the scores of these language tests would predict the differences in these tracts. We found significant alterations in language-related tracts such as inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UF) among three groups and between SIB and CON. We also proved partly their relationship with the language test as indicated by the significant correlation detected between TLI Impoverished thought/language sub-scale and ILF. We could not find any difference between FEP and CON. These results showed that the abnormalities, especially in the ILF and UF, could be important pathophysiological vulnerability indexes of schizophrenia. Further studies are required to understand better the role of language as a possible endophenotype in schizophrenia with larger samples.

Immunoinflammatory features and cognitive function in treatment-resistant schizophrenia: unraveling distinct patterns in clozapine-resistant patients.

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapine‑resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.

Verbal fluency in schizophrenia and bipolar disorder - A longitudinal, family study

Verbal fluency (VF) has been proposed as a putative neurocognitive endophenotype in schizophrenia (SZ) and bipolar disorder (BD). However, this hypothesis has not been examined using a longitudinal family approach. We conducted a five-group, comparative study. The sample comprised 323 adult participants, including 81 BD patients, 47 unaffected relatives of BD BD-Rel), 76 SZ patients, 40 unaffected relatives of SZ (SZ-Rel), and 79 genetically unrelated healthy controls (HC). All subjects were assessed twice with semantic VF (sem-VF) and phonological VF (ph-VF) tests over a 2-year follow-up period. ANCOVAs controlling for age and years of education were used to compare performance across groups. Patients with SZ and BD and their unaffected relatives showed sem-VF and ph-VF deficits at baseline, which persisted over time (all, p < 0.05). Moreover, BD-Rel showed an intermediate performance between SZ and HC. A repeated-measures ANOVA revealed no significant differences in the between-group trajectories comparison (p > 0.05). Our findings support that VF may represent a neurocognitive endophenotype for SZ and BD. Further longitudinal, family studies are warranted to confirm this preliminary evidence.

Resting State EEG Analysis for Schizophrenia: from Alpha-Rhythm Reduction to Microstates Assessment

Background: due to the emergence of new technologies for analyzing of EEG signal, many new researches in this field have appeared in recent years, including those investigating EEG parameters of schizophrenia. The aim: this publication provides an overview of actual studies on the possibilities of using the assessment of resting state EEG recordings in the diagnostics and prognosis of schizophrenia course. Material and methods: publications were selected in eLibrary, PubMed, Google Scholar and CNKI databases using the keywords: “psychosis”, “schizophrenia”, “EEG”, “resting state”. Methodologically, the atricle is a narrative literature review. Thirty-three sources were selected for analysis. Discussion and conclusion: according to the data available to present date qualitive and quantitative assessment of resting EEGs cannot be used for the instrumental diagnosis of schizophrenia because the most commonly detected increase in the proportion of slow-wave activity is seen in a several disorders. However, some quantitative spectral estimates of resting state EEG could be used to identify poor prognosis response to antipsychotic therapy, as well as for objective assessment of the dynamics of the mental state. Estimation of the power of slow resting EEG rhythms and other methods of assessing the connectivity of different neural networks could be considered as potential markers of the presence of a specific endophenotype. Modern digital technologies, including machine learning and artificial intelligence algorithms, make it possible to identify resting EEG of the schizophrenic patients from healthy controls with accuracy, sensitivity and specificity more than 95%. EEG microstates assessment, which can be used to assess the functioning of large neuronal ensembles, are one of the methods for detecting the endophenotype of schizophrenia.

The role of midbrain dopamine cells projecting to the insular cortex in mediated performance: Implications for animal models of reality testing.

A growing body of literature indicates that mediated learning techniques have specific utility for tapping into reality testing in animal models of neuropsychiatric illness. In particular, recent work has shown that animal models that recapitulate various endophenotypes of schizophrenia are particularly vulnerable to impairments in reality testing when undergoing mediated learning. Multiple studies have indicated that these effects are dopamine receptor 2-dependent and correlated with aberrant insular cortex (IC) activity. However, until now, the connection between dopamine and the IC had not been investigated. Here, we utilized a novel intersectional approach to label mesencephalic dopamine cells that specifically project to the insular cortex in both wild-type controls and transgenic mice expressing the dominant-negative form of the Disrupted-in-Schizophrenia-1 (DISC-1) gene. Using these techniques, we identified a population of cells that project from the ventral tegmental area (VTA) to the IC. Afterward, we conducted multiple studies to test the necessity of this circuit in behaviors ranging from gustatory detection to the maintenance of effort and, finally, mediated performance. Our results indicate that perturbations of the DISC-1 genetic locus lead to a reduction in the number of cells in the VTA → IC circuit. Behaviorally, VTA → IC circuitry does not influence gustatory detection or motivation to acquire sucrose reward; however, inactivation of this circuit differentially suppresses Pavlovian approach behavior in wild-type and DISC-1 transgenic mice during mediated performance testing. Moreover, under these testing conditions, inactivation of this circuit predisposes wild-type (but not DISC-1) mice to display impaired reality testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Childhood trauma and altered response of retinal neurons as an early risk endophenotype of schizophrenia and mood disorder

BackgroundExposure to childhood trauma may cause several alterations in brain structure and connectivity in adult patients having a major psychiatric disorder. Recent reports have shown that adult patients and young healthy offspring of patients carry similar abnormal retinal response. Because the retina and the brain have the same embryonic origin, the retina gives access to living neuronal tissue that may capture the early neurobiological effect of trauma. ObjectiveEvaluate the association between exposure to childhood trauma and anomalies in cone (photopic) and rod (scotopic) responses assessed by electroretinography (ERG) in children and adolescents at familial risk (FHRs) of psychosis or mood disorders. MethodsERG recordings (n=194) undertaken on 134 offspring (Mage of 1st recording=15.7, 49% females) enrolled in our longitudinal study and born to a parent having DSM-IV schizophrenia, bipolar disorder or major depressive disorder were analyzed using repeated measures linear mixed models and applying multiple comparisons. The scotopic and photopic a- and b-wave latencies and amplitudes were recorded. Five types of childhood trauma were assessed prospectively and retrospectively in FHRs: physical abuse, sexual abuse, emotional abuse, neglect and witnessing domestic violence. ResultsNone of the ERG scotopic or photopic parameters were associated with the global measure of exposure to trauma. However, when analyzing the specific effect of each type of trauma, data suggested that physical abuse in girls would be significantly associated with a prolonged scotopic a-wave latency (p=0.024, ES=0.28) and a trend of association was observed with a prolonged photopic b-wave latency (p=0.099, ES=0.27). ConclusionOur study did not suggest a substantial effect of childhood trauma on previously reported ERG anomalies in the cone and rod response in youth at familial risk of psychosis or mood disorder. Only one type of trauma i.e., physical violence toward the child, could have a specific effect on the cone and rod prolonged latencies in girls. Methodological limitations are discussed for consideration in interpreting the findings.

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

Polygenic effects on brain functional endophenotype for deficit and non-deficit schizophrenia

Deficit schizophrenia (DS) is a subtype of schizophrenia (SCZ). The polygenic effects on the neuroimaging alterations in DS still remain unknown. This study aims to calculate the polygenic risk scores for schizophrenia (PRS-SCZ) in DS, and further explores the potential associations with functional features of brain. PRS-SCZ was calculated according to the Whole Exome sequencing and Genome-wide association studies (GWAS). Resting-state fMRI, as well as biochemical features and neurocognitive data were obtained from 33 DS, 47 NDS and 41 HCs, and association studies of genetic risk with neuroimaging were performed in this sample. The analyses of amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were performed to detect the functional alterations between DS and NDS. In addition, correlation analysis was used to investigate the relationships between functional features (ALFF, ReHo, FC) and PRS-SCZ. The PRS-SCZ of DS was significantly lower than that in NDS and HC. Compared to NDS, there was a significant increase in the ALFF of left inferior temporal gyrus (ITG.L) and left inferior frontal gyrus (IFG.L) and a significant decrease in the ALFF of right precuneus (PCUN.R) and ReHo of right middle frontal gyrus (MFG.R) in DS. FCs were widely changed between DS and NDS, mainly concentrated in default mode network, including ITG, PCUN and angular gyrus (ANG). Correlation analysis revealed that the ALFF of left ITG, the ReHo of right middle frontal gyrus, the FC value between insula and ANG, left ITG and right corpus callosum, left ITG and right PCUN, as well as the scores of Trail Making Test-B, were associated with PRS-SCZ in DS. The present study demonstrated the differential polygenic effects on functional changes of brain in DS and NDS, providing a potential neuroimaging-genetic perspective for the pathogenesis of schizophrenia.

Anthranilic Acid, a GPR109A Agonist, and Schizophrenia.

Limited clinical efficiency of current medications warrants search for new antipsychotic agents. Deorphanized G-protein coupled receptor (GPR)109A has not attracted much of attention of schizophrenia researchers. We analyzed literature and our data on endogenous agonists of GPR109A, beta-hydroxybutyrate (BHB), anthranilic (AA), butyric (BA), and nicotinic (NA) acids, in individuals with schizophrenia. Sex specific differences: plasma AA levels were 27% higher in female than in male patients and correlated with PANSS before 6 weeks of antipsychotics treatment (r = .625, P < .019, Spearman's test). There was no sex specific differences of plasma AA levels after treatment. AA plasma levels inversely correlated (-.58, P < .005) with PANSS scores in responders to treatment (at least, 50% improvement) but not in nonresponders. Preclinical studies suggested antipsychotic effect of BHB and BA. Clinical studies observed antipsychotic effect of NA; benzoate sodium, an AA precursor; and interventions associated with BHB upregulation (eg, fasting and ketogenic diets). Upregulation of GPR109A, an anti-inflammatory and neuroprotective receptor, inhibits cytosolic phospholipase A2 (cPLA2), an enzyme that breakdown myelin, lipid-based insulating axonal sheath that protects and promotes nerve conduction. Brain cPLA2 is upregulated in individuals with schizophrenia and subjects at high-risk for development of psychosis. Lower myelin content is associated with cognitive decline in individuals with schizophrenia. Therefore, GPR109A might exert antipsychotic effect via suppression of cPLA2, and, consequently, preservation of myelin integrity. Future research might explore antipsychotic effects of (1) human pegylated kynureninase, an enzyme that catalyzes formation of AA from kynurenine (Kyn); (2) inhibitors of Kyn conversion into kynurenic acid, for example, KYN5356, to patients with already impaired Kyn conversion into 3-hydroxykynurenine; (3) synthetic GPR 109A agonists, for example, MK-1903 and SCH900271 and GSK256073, that underwent clinical trials as anti-dyslipidemia agents. GPR109A expression, that might be a new endophenotype of schizophrenia, especially associated with cognitive impairment, needs thorough assessment.

Co-expression of prepulse inhibition and Schizophrenia genes in the mouse and human brain

Schizophrenia is a complex psychiatric disorder with genetic and phenotypic heterogeneity. Accumulating rare and genome-wide association study (GWAS) common risk variant information has yet to yield robust mechanistic insight. Leveraging large-scale gene deletion mouse phenomic data thus has potential to functionally interrogate and prioritize human disease genes. To this end, we applied a cross-species network-based approach to parse an extensive mouse gene set (188 genes) associated with disrupted prepulse inhibition (PPI), a Schizophrenia endophenotype. Integrating PPI genes with high-resolution mouse and human brain transcriptomic data, we identified functional and disease coherent co-expression modules through hierarchical clustering and weighted gene co-expression network analysis (WGCNA). In two modules, Schizophrenia risk and mouse PPI genes converged based on telencephalic patterning. The associated neuronal genes were highly expressed in cingulate cortex and hippocampus; implicated in synaptic function and neurotransmission and overlapped with the greatest proportion of rare variants. Concordant neuroanatomical patterning revealed novel core Schizophrenia-relevant genes consistent with the Omnigenic hypothesis of complex traits. Among other genes discussed, the developmental and post-synaptic scaffold TANC2 (Tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2) emerged from both networks as a novel core genetic driver of Schizophrenia altering PPI. Aspects of psychiatric disease comorbidity and phenotypic heterogeneity are also explored. Overall, this study provides a framework and galvanizes the value of mouse preclinical genetics and PPI to prioritize both existing and novel human Schizophrenia candidate genes as druggable targets.

Altered HCAR3 expression may underlying the blunted niacin responses of the psychiatric disorders and the risk of schizophrenia.

Blunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients. Two independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT-PCR analysis, eQTL data, and Dual-Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR. The results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data. HCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In-depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.

Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia.

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.

The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK-801 model of schizophrenia-like cognitive inflexibility

Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization.The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus.The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801.These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.

The Association of the Oral Microbiota with the Effects of Acid Stress Induced by an Increase of Brain Lactate in Schizophrenia Patients.

The altered cerebral energy metabolism central to schizophrenia can be linked to lactate accumulation. Lactic acid is produced by gastrointestinal bacteria, among others, and readily crosses the blood-brain barrier, leading to the brain acidity. This study aimed to examine the association of the oral microbiota with the effects of acid stress induced by an increase of brain lactate in schizophrenia patients. The study included patients with a diagnosis of acute polyphasic psychotic disorder meeting criteria for schizophrenia at 3-month follow-up. Results: Individuals with a significantly higher total score on the Positive and Negative Syndrome Scale had statistically significantly lower lactate concentrations compared to those with a lower total score and higher brain lactate. We observed a positive correlation between Actinomyces and lactate levels in the anterior cingulate cap and a negative correlation between bacteria associated with lactate metabolism and some clinical assessment scales. Conclusions: Shifts in the oral microbiota in favour of lactate-utilising bacterial genera may represent a compensatory mechanism in response to increased lactate production in the brain. Assessment of neuronal function mediated by ALA-LAC-dependent NMDA regulatory mechanisms may, thus, support new therapies for schizophrenia, for which acidosis has become a differentiating feature of individuals with schizophrenia endophenotypes.

ГЕНЕТИЧЕСКИЕ МАРКЕРЫ ФАРМАКОКИНЕТИЧЕСКИХ ОСОБЕННОСТЕЙ У ПАЦИЕНТОВ С ТЯЖЕЛЫМ ИСХОДОМ ШИЗОФРЕНИИ, РЕЗИСТЕНТНЫХ К ТЕРАПИИ АНТИПСИХОТИКАМИ

The response to drug therapy is determined by the genetic characteristics of pharmacokinetic and pharmacodynamic processes in the human body. The study of the relationship between genetic factors and the resistance of patients with severe outcome is necessary to understand the causes of the formation of this endophenotype of schizophrenia. Our analysis showed a more frequent combination of a severe outcome of schizophrenia with alleles of genes that control the peripheral metabolism of xenobiotics and cause the pharmacokinetic processes of antipsychotic therapy.

Processing speed and psychomotor speed in first-episode of non-affective psychosis and first-degree relatives: a candidate endophenotype for schizophrenia

Processing speed and psychomotor speed in first-episode of non-affective psychosis and first-degree relatives: a candidate endophenotype for schizophrenia

Major neurocognitive psychosis: a novel schizophrenia endophenotype class that is based on machine learning and resembles Kraepelin's and Bleuler's conceptions.

The purpose of this study is to describe how to use the precision nomothetic psychiatry approach to (a) delineate the associations between schizophrenia symptom domains, including negative symptoms, psychosis, hostility, excitation, mannerism, formal thought disorders, psychomotor retardation (PHEMFP), and cognitive dysfunctions and neuroimmunotoxic and neuro-oxidative pathways and (b) create a new endophenotype class based on these features. We show that all symptom domains (negative and PHEMFP) may be used to derive a single latent trait called overall severity of schizophrenia (OSOS). In addition, neurocognitive test results may be used to extract a general cognitive decline (G-CoDe) index, based on executive function, attention, semantic and episodic memory, and delayed recall scores. According to partial least squares analysis, the impacts of adverse outcome pathways (AOPs) on OSOS are partially mediated by increasing G-CoDe severity. The AOPs include neurotoxic cytokines and chemokines, oxidative damage to proteins and lipids, IgA responses to neurotoxic tryptophan catabolites, breakdown of the vascular and paracellular pathways with translocation of Gram-negative bacteria, and insufficient protection through lowered antioxidant levels and impairments in the innate immune system. Unsupervised machine learning identified a new schizophrenia endophenotype class, named major neurocognitive psychosis (MNP), which is characterised by increased negative symptoms and PHEMFP, G-CoDe and the above-mentioned AOPs. Based on these pathways and phenome features, MNP is a distinct endophenotype class which is qualitatively different from simple psychosis (SP). It is impossible to draw any valid conclusions from research on schizophrenia that ignores the MNP and SP distinctions.

Can the Imbalance between Neurotrophic and Apoptotic Proteins Be the "Beware the Ides of March" for Unaffected Relatives of Schizophrenia Patients?

Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which are tPA-BDNF pathways proteins and arethought to play a role in synaptic pruning,as a possible endophenotype of schizophrenia. Forty drug-naïve patients with first-episode psychosis (FEP) matched for age, gender, and level of education, 40 unaffected siblings (UAS) of patients with FEP, and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH, and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway as well as the pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiate FEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the HCs with statistically significant differences between all 3 groups. The plasma level of pro-BDNF in the HC group was similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ and this imbalance could be an endophenotype of the disease.

Neurocognitive functioning in adult and adolescent offspring of parents with schizophrenia

IntroductionNeurocognitive deficits have been proposed as endophenotypes for schizophrenia. Although neurocognitive functioning has been studied extensively in first-degree relatives of schizophrenia patients at single time points, little is known about the change or continuity in deficits across development. MethodThe longitudinal sample was composed of 86 nonpsychotic participants who had a parent with schizophrenia (n = 28), a parent with a nonschizophrenia mental disorder (n = 31) or parents without mental illness (n = 27). Executive functioning (EF) was assessed during adolescence (M = 18 years) and adulthood (M = 32 years); attention and memory were assessed at adulthood. ResultsThe schizophrenia group, as adults, showed deficits in attention and memory relative to the no mental illness group. Only on one memory task did the schizophrenia group perform more poorly than the other mental illness group. Executive functioning improved with age for all three groups on Wisconsin Card Sorting Test perseverative errors; the rate of improvement was significantly slower for the schizophrenia and the other mental illness groups, compared to the no mental illness group. Stability in EF functioning over the 16-year period, measured by intraclass correlations, was low. ConclusionsAdults at familial risk for schizophrenia showed deficits in neurocognitive functioning. The similarity of performance between those whose parents had schizophrenia and those whose parents had other mental illness, in all but the measures of memory, raises the question as to whether the neurocognitive functions examined are endophenotypes of vulnerability to schizophrenia specifically. Modest stability of EF and improved performance with age may reflect cortical maturation during early adulthood.