Subgroup Of Schizophrenia Research Articles

Irregularity of visual motion perception and negative symptoms in schizophrenia.

Schizophrenia (SZ) is a severe psychiatric disorder characterized by perceptual, emotional, and behavioral abnormalities, with cognitive impairment being a prominent feature of the disorder. Recent studies demonstrate irregularity in SZ with increased variability on the neural level. Is there also irregularity on the psychophysics level like in visual perception? Here, we introduce a methodology to analyze the irregularity in a trial-by-trial way to compare the SZ and healthy control (HC) subjects. In addition, we use an unsupervised clustering algorithm K-means + + to identify SZ subgroups in the sample, followed by validation of the subgroups based on intraindividual visual perception variability and clinical symptomatology. The K-means + + method divided SZ patients into two subgroups by measuring durations across trials in the motion discrimination task, i.e., high, and low irregularity of SZ patients (HSZ, LSZ). We found that HSZ and LSZ subgroups are associated with more negative and positive symptoms respectively. Applying a mediation model in the HSZ subgroup, the enhanced irregularity mediates the relationship between visual perception and negative symptoms. Together, we demonstrate increased irregularity in visual perception of a HSZ subgroup, including its association with negative symptoms. This may serve as a promising marker for identifying and distinguishing SZ subgroups.

Higher levels of AKT-interacting protein in the frontal pole from people with schizophrenia are limited to a sub-group who have a marked deficit in cortical muscarinic M1 receptors

We are studying the molecular pathology of a sub-group within schizophrenia (∼ 25 %: termed Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS)) who can be separated because they have very low levels of cortical muscarinic M1 receptors (CHRM1). Based on our transcriptomic data from Brodmann's area ((BA) 9, 10 and 33 (controls, schizophrenia and mood disorders) and the cortex of the CHRM1−/− mouse (a molecular model of aberrant CHRM1 signaling), we predicted levels of AKT interacting protein (AKTIP), but not tubulin alpha 1b (TUBA1B) or AKT serine/threonine kinase 1 (AKT1) and pyruvate dehydrogenase kinase 1 (PDK1) (two AKTIP-functionally associated proteins), would be changed in MRDS. Hence, we used Western blotting to measure AKTIP (BA 10: controls, schizophrenia and mood disorders; BA 9: controls and schizophrenia) plus TUBA1B, AKT1 and PDK1 (BA 10: controls and schizophrenia) proteins. The only significant change with diagnosis was higher levels of AKTIP protein in BA 10 (Cohen's d = 0.73; p = 0.02) in schizophrenia compared to controls due to higher levels of AKTIP only in people with MRDS (Cohen's d = 0.80; p = 0.03). As AKTIP is involved in AKT1 signaling, our data suggests that signaling pathway is particularly disturbed in BA 10 in MRDS.

The novel schizophrenia subgroup “major neurocognitive psychosis” is validated as a distinct class through the analysis of immune-linked neurotoxicity biomarkers and neurocognitive deficits

BackgroundUsing machine learning methods based on neurocognitive deficits and neuroimmune biomarkers, two distinct classes were discovered within schizophrenia patient samples. Increased frequency of psychomotor retardation, formal thought disorders, mannerisms, psychosis, hostility, excitation, and negative symptoms defined the first subgroup, major neurocognitive psychosis (MNP). Cognitive deficits in executive functions and memory and diverse neuroimmune aberrations were other MNP features. Simple neurocognitive psychosis (SNP) was the less severe phenotype. AimsThe study comprised a sample of 40 healthy controls and 90 individuals diagnosed with schizophrenia, divided into MNP and SNP based on previously determined criteria. Soft Independent Modelling of Class Analogy (SIMCA) was performed using neurocognitive test results and measurements of serum M1 macrophage and T helper-17 cytokines as discriminatory/modelling variables. The model-to-model distances between controls and MNP + SNP and between MNP and SNP were computed, and the top discriminatory variables were established. ResultsA notable SIMCA distance of 146.1682 was observed between MNP + SNP and the control group. The top-3 discriminatory variables were lowered motor speed, an activated T helper-17 axis, and lowered working memory. This study successfully differentiated MNP from SNP yielding a SIMCA distance of 19.3. M1 macrophage activation, lowered verbal fluency, and executive functions were the prominent features of MNP versus SNP. DiscussionBased on neurocognitive assessments and the immune-linked neurotoxic M1 and T helper-17 profiles, we found that MNP and SNP are qualitatively distinct classes. Future biomarker research should focus on examining biomarkers specifically in the MNP and SNP subgroups, rather than in the schizophrenia group.

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation

A subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation (n = 13) and high inflammation (n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway ‘Hepatic Fibrosis/Hepatic Stellate-Cell Activation’. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix’s regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche.

Circulating microRNA Profiles Identify a Patient Subgroup with High Inflammation and Severe Symptoms in Schizophrenia Experiencing Acute Psychosis.

Schizophrenia is a complex and heterogenous psychiatric disorder. This study aimed to demonstrate the potential of circulating microRNAs (miRNAs) as a clinical biomarker to stratify schizophrenia patients and to enhance understandings of their heterogenous pathophysiology. We measured levels of 179 miRNA and 378 proteins in plasma samples of schizophrenia patients experiencing acute psychosis and obtained their Positive and Negative Syndrome Scale (PANSS) scores. The plasma miRNA profile revealed three subgroups of schizophrenia patients, where one subgroup tended to have higher scores of all the PANSS subscales compared to the other subgroups. The subgroup with high PANSS scores had four distinctively downregulated miRNAs, which enriched 'Immune Response' according to miRNA set enrichment analysis and were reported to negatively regulate IL-1β, IL-6, and TNFα. The same subgroup had 22 distinctively upregulated proteins, which enriched 'Cytokine-cytokine receptor interaction' according to protein set enrichment analysis, and all the mapped proteins were pro-inflammatory cytokines. Hence, the subgroup is inferred to have comparatively high inflammation within schizophrenia. In conclusion, miRNAs are a potential biomarker that reflects both disease symptoms and molecular pathophysiology, and identify a patient subgroup with high inflammation. These findings provide insights for the precision medicinal strategies for anti-inflammatory treatments in the high-inflammation subgroup of schizophrenia.

CPAN - A novel transdiagnostic dimensional approach to the assessment of psychotic disorders

IntroductionClassification of mental disorders evolved greatly over time, as DSM and ICD dominated both research and everyday practice in the past decades. DSM-5 was planned to represent biological features of psychiatric disorders and include results of genetic and imaging studies in the criteria. Unfortunately, this goal couldn’t be fulfilled, since, although there were promising results, evidence wasn’t strong enough to fully support the biological background of the currently used diagnostic categories. One possible explanation for this discrepancy is that biological disturbances don’t represent the somewhat artificial categorisation of these disorders. Many of the leading symptoms in psychotic disorders are nowadays considered as lying on a spectrum, such as autism, affective and psychotic spectrum disorders. Despite that, DSM-5 still describes schizophrenia, schizoaffective disorder and bipolar disorder as separate entities, however there can be major overlaps in the leading symptoms, moreover symptoms are not necessarily stable over time and can show fluctuations. It should be mentioned though that subgroups of schizophrenia in DSM-5 had been abolished and catatonia is considered as a trans-diagnostic specifier, moreover in ICD-11 certain symptoms can be added as symptoms specifiers to an existing diagnosis of primary psychotic disorder.ObjectivesOur aim was to establish a new trans-diagnostic, dimensional scale to assess the most important symptoms amongst patients with psychotic disorders. This scale is meant to represent the long-term clinical presentation and not a cross-sectional picture of a current state. We believe that long-term trajectories of these symptoms may be more connected to underlying biological features, such as genetic load (i.e. polygenic risk scores) and imaging results than the currently used diagnostic criteria. We think it is very important to create a tool, which is straightforward and short enough, so can be realistically used in everyday clinical work. This could provide important real-life data, which give us information about our patients from a different angle than the currently used diagnostic systems.MethodsWe have created the CPAN scale based on the current symptom specifiers of ICD-11 and the Clinician-Rated Dimensions of Psychosis Symptom Severity, which is an “emerging measure” for DSM-5 and also took into consideration our own clinical experience.ResultsThe new tool measures 4 symptoms (catatonia, psychosis, affective symptoms and negative symptoms) on a scale of 5 (0-4). We have also put in specifiers to be able to characterize patients more precisely, and output measures (suicidal risk, functionality) to open the way for further analysis.ConclusionsWe tried to establish a novel symptom scale to help assessing patients with psychotic symptoms in everyday clinical work. Our plan is to test the validity of CPAN in the near future.Disclosure of InterestNone Declared

Association between serum insulin-like growth factor 1 levels and the improvements of cognitive impairments in a subgroup of schizophrenia: Preliminary findings

BackgroundNumerous studies have implicated abnormal insulin-like growth factor 1 (IGF-1) in the pathophysiology of schizophrenia, but findings have been inconsistent. MethodsWe conducted a meta-analysis to compare IGF-1 levels in schizophrenia patients with healthy controls and explored factors contributing to variability between estimates. In an independent sample (58 chronic schizophrenia patients and 30 healthy controls), we investigated differences in IGF-1 levels among schizophrenia subgroups with distinct cognitive profiles, identified using k-means clustering based on five cognitive domains from The Repeatable Battery for the Assessment of Neuropsychological Status. Associations between serum IGF-1 levels and clinical and neurocognitive improvements were also examined. ResultsThe meta-analysis revealed significantly lower serum IGF-1 levels in schizophrenia patients compared to healthy controls, albeit with high heterogeneity. Medication status, BMI, and severity of negative symptoms were identified as potential contributors to this heterogeneity. In our independent study, antipsychotic treatment led to a significant increase in IGF-1 levels, and lower pre-treatment serum IGF-1 levels correlated with greater improvement in cognitive deficits, particularly in a subgroup with more severe cognitive symptoms. ConclusionsOur findings support the “IGF-1 deficiency hypothesis” in the pathogenesis of schizophrenia. Further research is crucial to elucidate the role of IGF-1 in the cognitive impairments associated with schizophrenia.

Clinical and cognitive characteristics of subjects with schizophrenia and childhood attention-deficit/hyperactivity disorder: Results from the multicentric FACE-SZ cross-sectional dataset

BackgroundChildhood Attention-deficit/hyperactivity disorder (C-ADHD) is a neurodevelopmental disorder, associated with an increased risk of subsequent schizophrenia. The objective of the present study was to determine the prevalence of C-ADHD in schizophrenia and the clinical and cognitive characteristics associated with C-ADHD history in schizophrenia. Methods569 subjects with schizophrenia (74 % men, mean age 30.8) were included in ten expert centers at a national level and tested with a comprehensive battery of clinician-rated, patient-reported scales and cognitive tests. C-ADHD was assessed with the WURS (Wender Utah Rating Scale) self-report questionnaire. Multivariate, correlation, and principal component analyses (PCA) were conducted. ResultsThirty-nine subjects (N = 39, 6.9 %) were classified in the C-ADHD group. Compared to those without C-ADHD, subjects with C-ADHD were more frequently male, had lower education levels, more severe positive clinical symptoms, more subjective cognitive deficits complaints, and lower medication adherence with small to medium effect sizes. Two cognitive components emerged from the PCA, one component including perceptual reasoning and working memory, and another component including visuospatial search and graphomotor speed, cognitive inhibition/flexibility and central executive functioning. Both components were associated with lower performances in the C-ADHD group. ConclusionsC-ADHD is frequent in schizophrenia and associated with more severe positive symptoms and impaired cognitive performances compared to those without C-ADHD. This suggests that the pathophysiological mechanisms contributing to these disorders may lead to the worsening of the cognitive functioning in patients with both disorders. C-ADHD is a relevant clinical marker to discriminate subgroups of schizophrenia with different profiles for a precision-psychiatry approach.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

Free water alterations in different inflammatory subgroups in schizophrenia

BackgroundAccumulating evidence suggests that inflammatory dysregulation both in blood and the brain is implicated in the pathogenesis of schizophrenia. Alterations in peripheral cytokines are not evident in all patients and there may be discrete altered inflammatory subgroups in schizophrenia. Recent studies using a novel and in vivo free-water imaging to detect inflammatory processes, have shown increased free water in white matter in schizophrenia. However, no studies to date have investigated the free water alterations in different inflammatory subgroups in schizophrenia. MethodsForty-four patients with schizophrenia and 49 controls were recruited. The serum levels of interleukin-1 beta (IL-1β), IL-6, IL-10, and IL-12p70 were measured and used for cluster analysis with K-means and hierarchical algorithms. Diffusion tensor imaging (DTI) images were collected for all participants and voxel-wise free water and fractional anisotropy of tissue (FA-t) were compared between groups with Randomise running in FSL. Partial correlation analysis was employed to explore the association of the peripheral cytokine levels with free water. ResultsWe identified two statistically quantifiable discrete subgroups of patients based on the cluster analysis of cytokine measures. The peripheral levels of IL-1β (P < 0.001), IL-10 (P = 0.041), and IL-12p70 (P < 0.001) showed significant differences between the two different inflammatory subgroups. In the inflammatory subgroup with a predominantly higher IL-1β level, increased free water values in white matter were found mainly in the left posterior limb of the internal capsule, posterior corona radiata, and partly in the left sagittal stratum. These affected areas did not overlap with the regions that showed significant free water differences between patients and healthy controls. In the inflammatory subgroup with lower IL-1β levels, peripheral IL-1β was significantly associated with free water values in white matter while no such association was detected in the patient group. ConclusionsLocalized free water differences were demonstrated between the two identified inflammatory subgroups in our data, and free water appears to be a feasible in vivo neuroimaging biomarker guiding the target of inflammatory intervention and development of new therapeutic strategies in an individualized manner in schizophrenia.

Digital behavioural signatures reveal trans-diagnostic clusters of Schizophrenia and Alzheimer's disease patients

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.

Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors.

Schizophrenia is associated with increased risk of cardiovascular disease (CVD), although there is variation in risk among individuals. There are indications of shared genetic etiology between schizophrenia and CVD, but the nature of the overlap remains unclear. The aim of this study was to fill this gap in knowledge. Overlapping genetic architectures between schizophrenia and CVD risk factors were assessed by analyzing recent genome-wide association study (GWAS) results. The bivariate causal mixture model (MiXeR) was applied to estimate the number of shared variants and the conjunctional false discovery rate (conjFDR) approach was used to pinpoint specific shared loci. Extensive genetic overlap was found between schizophrenia and CVD risk factors, particularly smoking initiation (N=8.6K variants) and body mass index (BMI) (N=8.1K variants). Several specific shared loci were detected between schizophrenia and BMI (N=304), waist-to-hip ratio (N=193), smoking initiation (N=293), systolic (N=294) and diastolic (N=259) blood pressure, type 2 diabetes (N=147), lipids (N=471), and coronary artery disease (N=35). The schizophrenia risk loci shared with smoking initiation had mainly concordant effect directions, and the risk loci shared with BMI had mainly opposite effect directions. The overlapping loci with lipids, blood pressure, waist-to-hip ratio, type 2 diabetes, and coronary artery disease had mixed effect directions. Functional analyses implicated mapped genes that are expressed in brain tissue and immune cells. These findings indicate a genetic propensity to smoking and a reduced genetic risk of obesity among individuals with schizophrenia. The bidirectional effects of the shared loci with the other CVD risk factors may imply differences in genetic liability to CVD across schizophrenia subgroups, possibly underlying the variation in CVD comorbidity.

Relation of Vitamin D levels with positive and negative symptoms of schizophrenia - A hospital based cross-sectional comparative study.

The association between altered serum Vitamin D levels and schizophrenia has been an area that has evoked a recent fervor. The neurohumoral and neuro immunomodulatory functions of Vitamin D might have a role to play in understanding the causation of the disease and thus appear promising in the diagnostic and therapeutic frontiers of the disease. We aimed to estimate and compare serum Vitamin D levels in drug-free cases of schizophrenia and in healthy control groups. The comparison was also made among the subgroups of positive and negative schizophrenia. The study, a hospital-based cross-sectional comparative study was carried out in the Department of Psychiatry, in a hospital in Assam over a period of 1 year. Fifty drug-free subjects of schizophrenia (Group A) diagnosed and confirmed according to International Classification of Diseases 10 were selected by consecutive sampling and 50 age and sex frequency-matched subjects (Group B) were selected from the healthy population. The cases (Group A) were divided into positive and negative groups (Group A1 and A2) based on the composite scoring of the Positive and Negative Syndrome Scale. After approval from the institutional ethics committee and obtaining written informed consent, Vitamin D levels were assessed in both groups of cases and controls and comparison was made. After statistical analysis, it was seen that males were more in proportion and mostly in the age group of 20-39 years. The median Vitamin D level among the cases was 12.45 ng/mL and that among controls was 20.03 ng/mL which was statistically significant (P value .00932). Among the positive and negative schizophrenia subgroup, there was no statistically significant difference in Vitamin D levels at means of 16.54 ng/mL and 16.25 ng/Ml, respectively. The variation in Vitamin D levels in schizophrenics and the healthy population is thus discernible. It can be said that serum Vitamin D levels were significantly low in people with schizophrenia compared to the general population. Furthermore, it is seen that mean Vitamin D status is similar in both the groups of positive and negative schizophrenia negating the possibility of alteration of Vitamin D levels depending on the differences in symptomatology or in pathophysiology of the two groups.

Evidence for increased DNA damage repair in the postmortem brain of the high stress-response group of schizophrenia.

Schizophrenia (SZ) is a disorder diagnosed by specific symptoms and duration and is highly heterogeneous, clinically and pathologically. Although there are an increasing number of studies on the association between genetic and environmental factors in the development of SZ, the actual distribution of the population with different levels of influence of these factors has not yet been fully elucidated. In this study, we focused on stress as an environmental factor and stratified SZ based on the expression levels of stress-responsive molecules in the postmortem prefrontal cortex. We selected the following stress-responsive molecules: interleukin (IL) -1β, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, glucocorticoid receptor, brain-derived neurotrophic factor, synaptophysin, S100 calcium-binding protein B, superoxide dismutase, postsynaptic density protein 95, synuclein, apolipoprotein A1 (ApoA1), ApoA2, and solute carrier family 6 member 4. We performed RNA sequencing in the prefrontal gray matter of 25 SZ cases and 21 healthy controls and conducted a hierarchical cluster analysis of SZ based on the gene expression levels of stress-responsive molecules, which yielded two clusters. After assessing the validity of the clusters, they were designated as the high stress-response SZ group and the low stress-response SZ group, respectively. Ingenuity Pathway Analysis of differentially expressed genes (DEGs) between clusters was performed, and Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was conducted on four cases each in the high and low stress-response SZ groups to validate DNA damage. We found higher prevalence of family history of SZ in the low stress-response SZ group (0/3 vs. 5/4, p = 0.04). Pathway analysis of DEGs between clusters showed the highest enrichment for DNA double-strand break repair. TUNEL staining showed a trend toward a lower percentage of TUNEL-positive cells in the high stress-response SZ group. Our results suggest that there are subgroups of SZ with different degrees of stress impact. Furthermore, the pathophysiology of these subgroups may be associated with DNA damage repair. These results provide new insights into the interactions and heterogeneity between genetic and environmental factors.

Exploring negative symptoms heterogeneity in patients diagnosed with schizophrenia and schizoaffective disorder using cluster analysis

BackgroundDissecting the heterogeneity of schizophrenia may help foster progress in understanding its etiology and lay the groundwork for the development of new treatment options for primary or enduring negative symptoms (NS). In this regard, the present study aimed to: (1) to use cluster analysis to identify subgroups of Lebanese patients diagnosed with either schizophrenia or schizoaffective disorder based on NS clusters, and (2) to relate the statistically-derived subgroups to clinically relevant external validators (including measures if state and trait depression, stigma, insight, loneliness, social support).MethodA total of 202 adult long-stay, chronic, and clinically remitted patients (166 diagnosed with schizophrenia and 36 with schizoaffective disorder) were enrolled. A cluster analysis approach was adopted to classify patients based on the five NS domains social withdrawal, emotional withdrawal, alogia, avolition and anhedonia.ResultsA three-cluster solution was obtained based on unique NS profiles, and divided patients into (1) low NS (LNS; 42.6%) which characterized by the lowest mean scores in all NS domains, (2) moderate NS (MNS; 25.7%), and (3) high NS (HNS; 31.7%). Post-hoc comparisons showed that depression (state and trait), loneliness and social support could accurately distinguish the schizophrenia subgroups. Additionally, individuals in the HNS cluster had longer duration of illness, longer duration of hospitalization, and were given higher dosages of antipsychotic medication compared to those in the other clusters, but these differences did not achieve the statistical significance.ConclusionFindings provide additional support to the categorical model of schizophrenia by confirming the existence of three alternate subtypes based on NS. The determination of distinct NS subgroups within the broad heterogeneous population of people diagnosed with schizophrenia may imply that each subgroup possibly has unique underlying mechanisms and necessitates different treatment approaches.

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity

ObjectiveImmune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. MethodsThe total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. ResultsAn optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. ConclusionsInflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities.

Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%-59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

Late-onset psychose: een diagnostische en therapeutische uitdaging voor de clinicus

Late-onset psychosis: a diagnostic and therapeutic challenge for the clinician In clinical practice, doctors are frequently confronted with psychosis in the elderly (above 60 years). This symptomatology presents a diagnostic and therapeutic challenge for the clinician. Its cause may be primarily psychiatric or secondary to a somatic or neurological disorder. In this article, the case of an elderly woman presenting with typical partition delusions (the belief that something or someone exerts influence through impermeable structures) is described. This case illustrates the difficult differential diagnosis between primary psychiatric disorders and neurocognitive disorders with late-onset psychotic symptoms, as well as the discussion concerning the nosological classification of schizophrenia in the elderly population. At the end of the 20th century, the term ‘very late-onset schizophrenia-like psychosis’ was introduced for schizophrenia-like psychotic symptoms developing after the age of 60. To this day, the validity of the existence and the etiology of this subgroup of schizophrenia remain a matter of debate. Psychosocial interventions are the first step in the treatment of late-onset psychotic symptoms. The use of antipsychotics is reserved for persistent, severe and debilitating symptoms because of the many side effects in the elderly population. However, the symptoms are often intrusive and have a negative impact on general functioning, so that drug treatment is regularly used in clinical practice.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Emotion-behaviour decoupling and experiential pleasure deficits predict negative symptoms and functional outcome in first-episode schizophrenia patients.

Emotion-behaviour decoupling refers to the failure to translate emotion into motivated behaviour, and is a putative marker for schizophrenia. The heterogeneity of experiential pleasure and emotion expressivity deficits has been reported in schizophrenia patients. These three constructs are believed to contribute to negative symptoms, but very few studies have examined their predictive ability for clinical and functional outcome of schizophrenia. This study aimed to clarify whether these three constructs influence clinical and functional outcome of schizophrenia. At baseline, 127 first-episode schizophrenia patients completed a behavioural paradigm for emotion-behaviour decoupling, and self-report scales for experiential pleasure and emotion expressivity deficits. Cluster-analysis was applied to characterize schizophrenia subgroups based on these three constructs. At end-point (mean follow-up = 5.37 years, SD = 1.03 years), 85 schizophrenia patients were reassessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and a clinician-rated social functioning scale. Cluster 1 (n=74) did not show emotion-behaviour decoupling, and had intact experiential pleasure and emotion expressivity. Cluster 2 (n=29) showed emotion-behaviour decoupling and experiential pleasure deficits. Cluster 3 (n=24) showed emotion expressivity deficits. At endpoint, the three clusters differed significantly in CAINS MAP factor (p=0.016) and social functioning (p=0.019), but not CAINS EXP factor. Specifically, Cluster 2 (n=18) showed more severe negative symptoms of CAINS MAP factor (p=0.046) and poorer social functioning (p=0.022) than Cluster 1 (n=49). Cluster 3 (n=18) did not differ from Cluster 1 and Cluster 2 in negative symptoms and social functioning. Emotion-behaviour decoupling and experiential pleasure deficits predicted clinical and functional outcome of schizophrenia.