Lipid Alteration Signature in the Blood Plasma of Individuals With Schizophrenia, Depression, and Bipolar Disorder.

Importance: No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. Objective: To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD). Design, Setting, and Participants: This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020. Main Outcomes and Measures: Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry. Results: Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids. Conclusions and Relevance: In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.

Stability over time of scores on psychiatric rating scales, questionnaires and cognitive tests in healthy controls.

BACKGROUND: Case-only longitudinal studies are common in psychiatry. Further, it is assumed that psychiatric ratings and questionnaire results of healthy controls stay stable over foreseeable time ranges. For cognitive tests, improvements over time are expected, but data for more than two administrations are scarce. AIMS: We comprehensively investigated the longitudinal course for trends over time in cognitive and symptom measurements for severe mental disorders. Assessments included the Trail Making Tests, verbal Digit Span tests, Global Assessment of Functioning, Inventory of Depressive Symptomatology, the Positive and Negative Syndrome Scale, and the Young Mania Rating Scale, among others. METHOD: Using the data of control individuals (n = 326) from the PsyCourse study who had up to four assessments over 18 months, we modelled the course using linear mixed models or logistic regression. The slopes or odds ratios were estimated and adjusted for age and gender. We also assessed the robustness of these results using a longitudinal non-parametric test in a sensitivity analysis. RESULTS: Small effects were detected for most cognitive tests, indicating a performance improvement over time (P < 0.05). However, for most of the symptom rating scales and questionnaires, no effects were detected, in line with our initial hypothesis. CONCLUSIONS: The slightly but consistently improved performance in the cognitive tests speaks of a test-unspecific positive trend, while psychiatric ratings and questionnaire results remain stable over the observed period. These detectable improvements need to be considered when interpreting longitudinal courses. We therefore recommend recruiting control participants if cognitive tests are administered.

A novel longitudinal clustering approach to psychopathology across diagnostic entities in the hospital-based PsyCourse study.

Biological research and clinical management in psychiatry face two major impediments: the high degree of overlap in psychopathology between diagnoses and the inherent heterogeneity with regard to severity. Here, we aim to stratify cases into homogeneous transdiagnostic subgroups using psychometric information with the ultimate aim of identifying individuals with higher risk for severe illness. 397 participants of the PsyCourse study with schizophrenia- or bipolar-spectrum diagnoses were prospectively phenotyped over 18 months. Factor analysis of mixed data of different rating scales and subsequent longitudinal clustering were used to cluster disease trajectories. Five clusters of longitudinal trajectories were identified in the psychopathologic dimensions. Clusters differed significantly with regard to Global Assessment of Functioning, disease course, and-in some cases-diagnosis while there were no significant differences regarding sex, age at baseline or onset, duration of illness, or polygenic burden for schizophrenia. Longitudinal clustering may aid in identifying transdiagnostic homogeneous subgroups of individuals with severe psychiatric disease.

Medication Adherence in a Cross-Diagnostic Sample of Patients From the Affective-to-Psychotic Spectrum: Results From the PsyCourse Study.

INTRODUCTION: According to the World Health Organization, medication adherence is defined as the extent to which a person's behavior corresponds with an agreed recommendation from a healthcare provider. Approximately 50% of patients do not take their medication as prescribed, and non-adherence can contribute to the progress of a disease. For patients suffering from mental diseases non-adherence plays an important role. Various factors have been proposed as contributing to non-adherence, however the literature remains heterogeneous dependent on the analyzed patient subgroups. This study comprehensively evaluates the association of sociodemographic, clinical, personality and quality of life related factors with medication adherence by analyzing data from the PsyCourse study. The PsyCourse study is a large and cross-diagnostic cohort of psychiatric patients from the affective-to-psychotic spectrum. METHODS: The study sample comprised 1,062 patients from the PsyCourse study with various psychiatric diagnoses (mean [SD] age, 42.82 [12.98] years; 47.4% female). Data were analyzed to identify specific factors associated with medication adherence, and adherence was measured by a self-rating questionnaire. Odds ratios (OR) were estimated by a logistic regression for binary outcomes. Missing data were imputed using multiple imputation. RESULTS: The following factors showed the strongest association with medication adherence: never having used illicit drugs (OR, 0.71), number of prescribed antipsychotics (OR, 1.40), the personality trait conscientiousness (OR, 1.26), and the environmental domain of quality of life (OR, 1.09). CONCLUSION: In a large and cross-diagnostic sample, we could show that a higher level of conscientiousness, a higher number of antipsychotic medication, a better quality of life within the environmental domain, and the absence of substance abuse contribute to a better medication adherence independent of the underlying disorder.

Interplay between the genetics of personality traits, severe psychiatric disorders and COVID-19 host genetics in the susceptibility to SARS-CoV-2 infection.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, with its impact on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behaviour and, therefore, the risk of contracting the virus. AIMS: We examined overlapping genetic underpinnings between major psychiatric disorders, personality traits and susceptibility to SARS-CoV-2 infection. METHOD: Linkage disequilibrium score regression was used to explore the genetic correlations of coronavirus disease 2019 (COVID-19) susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n = 1346) and the HeiDE (n = 3266) study), polygenic risk scores were used to analyse if a genetic association between, psychiatric disorders, personality traits and COVID-19 susceptibility exists in individual-level data. RESULTS: We observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (P = 1.47 × 10-5; genetic correlation 0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies. CONCLUSIONS: We identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders.

A genome-wide association study of the longitudinal course of executive functions.

Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10-10 with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics.

Polygenic risk scores across the extended psychosis spectrum.

As early detection of symptoms in the subclinical to clinical psychosis spectrum may improve health outcomes, knowing the probabilistic susceptibility of developing a disorder could guide mitigation measures and clinical intervention. In this context, polygenic risk scores (PRSs) quantifying the additive effects of multiple common genetic variants hold the potential to predict complex diseases and index severity gradients. PRSs for schizophrenia (SZ) and bipolar disorder (BD) were computed using Bayesian regression and continuous shrinkage priors based on the latest SZ and BD genome-wide association studies (Psychiatric Genomics Consortium, third release). Eight well-phenotyped groups (n = 1580; 56% males) were assessed: control (n = 305), lower (n = 117) and higher (n = 113) schizotypy (both groups of healthy individuals), at-risk for psychosis (n = 120), BD type-I (n = 359), BD type-II (n = 96), schizoaffective disorder (n = 86), and SZ groups (n = 384). PRS differences were investigated for binary traits and the quantitative Positive and Negative Syndrome Scale. Both BD-PRS and SZ-PRS significantly differentiated controls from at-risk and clinical groups (Nagelkerke's pseudo-R2: 1.3-7.7%), except for BD type-II for SZ-PRS. Out of 28 pairwise comparisons for SZ-PRS and BD-PRS, 9 and 12, respectively, reached the Bonferroni-corrected significance. BD-PRS differed between control and at-risk groups, but not between at-risk and BD type-I groups. There was no difference between controls and schizotypy. SZ-PRSs, but not BD-PRSs, were positively associated with transdiagnostic symptomology. Overall, PRSs support the continuum model across the psychosis spectrum at the genomic level with possible irregularities for schizotypy. The at-risk state demands heightened clinical attention and research addressing symptom course specifiers. Continued efforts are needed to refine the diagnostic and prognostic accuracy of PRSs in mental healthcare.

Dysconnectivity of the inferior frontal gyrus: implications for an impaired self-other distinction in patients with schizophrenia.

Ego disturbances in schizophrenia might be caused by a failure of the efference copy mechanism, which compares efferent with reafferent signals and attenuates the sensory consequences of self-produced movements. We carried out a functional magnetic resonance imaging study in which 16 patients with schizophrenia and 16 healthy matched controls were studied while performing both intentional and unintentional continuous hand movements in two consecutive experiments. We periodically varied the delay of visual feedback to create a sensory-motor discrepancy. Exclusively for intentional movements the activation pattern of the inferior frontal gyrus (IFG) in patients was opposite to that of controls: less attenuated during time-congruent feedback and less activated during time-incongruent feedback. Additionally, several functional connections within the mismatch detection network (IFG with insula, putamen, medial orbitofrontal cortex) were affected. Also, activity of the dysconnected orbitofrontal cortex was correlated with ego disturbance in patients. We discuss that in healthy individuals the IFG might enable a distinction between self and non-self using time-characteristics of feedback, whereas in patients this sensory mismatch detection appears to be altered. Moreover, due to the dysconnectivity of the IFG, the efferent and reafferent signal exchange between perceptual and motor areas seems to be affected. This might cause self-monitoring deficits in patients, phenomena that contribute to the emergence of ego disturbances.

Hyperintentionality during automatic perception of naturalistic cooperative behavior in patients with schizophrenia.

Social cognition and the corresponding functionality of involved brain networks are essential for effortless social interaction. Patients with schizophrenia exhibit impaired social functioning. In this study, we focused on the neural networks involved in the automatic perception of cooperative behavior and their alterations in schizophrenia. We performed a functional magnetic resonance imaging study of 19 schizophrenia patients and 19 healthy matched controls. Participants watched a set of short videos with two actors manipulating objects, either with (C+) or without cooperation (C-). Additionally, we assessed delusional symptoms in patients using the Scales for the Assessment of Positive Symptoms and psychosis proneness in healthy controls using the brief schizotypal personality questionnaire. The observed group-by-condition interaction revealed a contrasting activation pattern for patients versus healthy controls in the medial and lateral prefrontal cortex, the middle cingulate cortex, and the left angular gyrus. Furthermore, increased activation of the middle prefrontal areas, left angular gyrus, and the posterior sulcus temporalis superior in response to the noncooperative condition (C-) was positively correlated with delusional symptoms in patients. Our findings suggest an overactivated "theory of mind" network in patients for the processing of noncooperative behavior. Thus, "overmentalizing" might be based on delusions and altered processing of cooperative behavior in patients with schizophrenia.

Maintaining hepatocyte differentiation in vitro through co-culture with hepatic stellate cells.

Primary hepatocytes lose their differentiated functions rapidly when in culture. Our aim was to maintain the differentiated status of hepatocytes in vitro by means of vital hepatic stellate cells (HSCs), their soluble and particulate factors and lipid extracts. Hepatocytes were placed into collagen-coated culture dishes in the presence of HSCs at different ages of pre-culture, with or without direct cell to cell contacts, at different cell ratios and in monoculture with cellular HSC components in place of vital cells. Changes in morphology and enhancement of phosphoenolpyruvate carboxykinase (PCK) activity by glucagon were used to determine the differentiated status of hepatocytes in 2d-short-term culture. HSCs proved able to maintain the differentiated function of hepatocytes in co-culture either by direct cell contacts or via factors derived from HSC-conditioned medium. In comparison, however, without cellular contact to hepatocytes five to ten times as many HSCs were necessary to increase the PCK activity to the same degree as in the presence of intercellular contacts. Whereas stimulation in the presence of HSC/hepatocyte contacts was independent of HSC culture age only quiescent, resting HSCs (precultured for 1-2 d) were able to stimulate hepatocytes significantly via soluble factors. Culturing of hepatocytes with a lipid extract or a particulate fraction from HSCs clearly displayed a very strong beneficial effect on enzyme activity and morphology. HSCs maintain hepatocyte function and structure through preferentially cell-bound signalling and transfer of lipids.