Serum Levels of the Steroid Hormone Dehydroepiandrosterone Are Associated with Psychological Trauma and Lymphocyte Telomere Integrity in Women Suffering from Depression.

INTRODUCTION: Emerging studies highlight the telomere system as an aging mechanism underlying the association between exposure to psychological trauma and the development of a wide range of physical and mental disorders, including major depressive disorder (MDD). Here, we investigated associations of circulating levels of the steroid hormone dehydroepiandrosterone (DHEA) with immune cell telomere length (TL) in the context of lifetime trauma exposure and MDD. METHODS: Lifetime traumatic events (trauma load) were assessed using the Essener Trauma Inventory in n = 22 postmenopausal female inpatients with MDD and n = 22 non-depressed controls. All women completed the Beck's Depression Inventory II to assess the severity of current depressive symptoms. DHEA concentration in serum was measured by immunoassay, and TL was quantified in kilobase units using quantitative fluorescent in situ hybridization in total peripheral blood mononuclear cells (PBMC) and in selected T-cell subpopulations isolated by FACS separation. RESULTS: Higher trauma load was significantly associated with lower DHEA concentration, which in turn was linked to more depression-related fatigue. Furthermore, DHEA concentration was positively and significantly associated with TL in memory CD4+ T cells as well as in naïve and memory CD8+ T cells, but not in naïve CD4+ T cells and total PBMC. Mediational analysis suggested that DHEA concentration is a mediator in the relationship between trauma load and memory CD8+ T-cell TL. CONCLUSION: The current findings suggest a potential role of DHEA as a biological resilience factor that may exert beneficial effects on telomere integrity, especially in conditions related to distress.

Word recognition memory and serum levels of Borna disease virus specific circulating immune complexes in obsessive-compulsive disorder.

BACKGROUND: Borna disease virus 1 (BoDV-1) is a non-segmented, negative-strand RNA virus that persistently infects mammals including humans. BoDV-1 worldwide occurring strains display highly conserved genomes with overlapping genetic signatures between those of either human or animal origin. BoDV-1 infection may cause behavioral and cognitive disturbances in animals but has also been found in human major depression and obsessive-compulsive disorder (OCD). However, the impact of BoDV-1 on memory functions in OCD is unknown. METHOD: To evaluate the cognitive impact of BoDV-1 in OCD, event-related brain potentials (ERPs) were recorded in a continuous word recognition paradigm in OCD patients (n = 16) and in healthy controls (n = 12). According to the presence of BoDV-1-specific circulating immune complexes (CIC), they were divided into two groups, namely group H (high) and L (low), n = 8 each. Typically, ERPs to repeated items are characterized by more positive waveforms beginning approximately 250 ms post-stimulus. This "old/new effect" has been shown to be relevant for memory processing. The early old/new effect (ca. 300-500 ms) with a frontal distribution is proposed to be a neural correlate of familiarity-based recognition. The late old/new effect (post-500 ms) is supposed to reflect memory recollection processes. RESULTS: OCD patients were reported to show a normal early old/new effect and a reduced late old/new effect compared to normal controls. In our study, OCD patients with a high virus load (group H) displayed exactly these effects, while patients with a low virus load (group L) did not differ from healthy controls. CONCLUSION: These results confirmed that OCD patients had impaired memory recollection processes compared to the normal controls which may to some extent be related to their BoDV-1 infection.

Reduced Jumping to Conclusion Bias after Experimentally Induced Enhancement of Subjective Body Boundaries in Psychosis.

INTRODUCTION: A disturbed sense of self is frequently discussed as an etiological factor for delusion symptoms in psychosis. Phenomenological approaches to psychopathology posit that lacking the sense that the self is localized within one's bodily boundaries (disembodiment) is one of the core features of the disturbed self in psychosis. The present study examines this idea by experimentally manipulating the sense of bodily boundaries. METHODS: Seventy-three patients with psychosis were randomly assigned to either a 10-min, guided self-massage in the experimental group (EG) to enhance the sense of bodily boundaries or a control group (CG), which massaged a fabric ring. Effects on an implicit measure (jumping to conclusion bias; JTC) and an explicit measure (Brief State Paranoia Checklist; BSPC) of delusion processes were assessed. The JTC measures the tendency to make a decision with little evidence available, and the BSPC explicitly measures the approval of paranoid beliefs. RESULTS: Patients in the EG showed a lower JTC (M = 4.11 draws before decision) than the CG (M = 2.43; Cohen's d = 0.64). No significant difference in the BSPC was observed. DISCUSSION/CONCLUSION: Our results indicate that enhancing the sense of body boundaries through a self-massage can reduce an implicit bias associated with delusional ideation and correspondingly support the idea that disembodiment might be a relevant factor in the formation of psychotic symptoms.

HDAC1 links early life stress to schizophrenia-like phenotypes.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

A longitudinal approach to biological psychiatric research: The PsyCourse study.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genomic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study (N = 891 individuals at baseline), an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. To provide an initial characterization of the PsyCourse study sample, we compare two broad diagnostic groups defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) classification system, that is, predominantly affective (n = 367 individuals) versus predominantly psychotic disorders (n = 524 individuals). Depressive, manic, and psychotic symptoms as well as global functioning over time were contrasted using linear mixed models. Furthermore, we explored the effects of polygenic risk scores for schizophrenia on diagnostic group membership and addressed their effects on nonparticipation in follow-up visits. While phenotypic results confirmed expected differences in current psychotic symptoms and global functioning, both manic and depressive symptoms did not vary between both groups after correction for multiple testing. Polygenic risk scores for schizophrenia significantly explained part of the variability of diagnostic group. The PsyCourse study presents a unique resource to research the complex relationships of psychopathology and biology in severe mental disorders not confined to traditional diagnostic boundaries and is open for collaborations.

The beneficial and detrimental effects of major depression on intuitive decision-making.

Intuitions play a central role in everyday life decision-making but little is known regarding this capacity during depression. Thus, in Study 1, N = 39 depressed in-patients completed two well-established tasks, assessing intuitions of visual and semantic coherence. In the semantic coherence task, patients judged whether presented words triads were coherent (e.g. SALT DEEP FOAM, related to SEA) or not (e.g. DREAM BALL BOOK, no denominator). In the visual coherence task, patients judged whether blurred pictures depicted real-life objects (coherent) or not (incoherent). Results showed that higher depressive symptomatology was associated with impaired intuitions of semantic coherence but with enhanced intuitions of visual coherence. In Study 2, visual coherence intuitions of depressed patients (n = 27) were compared to healthy control participants (n = 30). Depressed patients outperformed the healthy control subjects in the visual coherence task. This pattern of findings shows both detrimental and beneficial decisional consequences of depression.

Impaired intuition in patients with major depressive disorder.

OBJECTIVES: In daily life, many decisions of minor and major importance have to be made. Thereby, intuitive judgments serve as useful guides and help us to adapt to our environment. People with major depressive disorder (MDD) often have difficulties to come to decisions. Is their intuition impaired? Since this question has not been addressed until now, the present study explored intuition in MDD. METHODS: Depressed patients (n = 29) and healthy control participants (n = 27) completed the Judgment of Semantic Coherence Task, a well-established paradigm used in basic cognitive research to measure intuition. Furthermore, participants' severity of depressive symptoms (BDI-II), negative affect (PANAS), and rumination (RSQ) were assessed. All participants were interviewed with the SCID. RESULTS: Depressed patients showed impaired intuition compared to healthy control participants. In the depressed sample, negative affect accounts for the association between rumination and impaired intuition. Results further reveal that negative affect overall mediates the depression-intuition relationship. Patients with diminished ability to concentrate or indecisiveness had lower intuition indices compared to patients who did not fulfil this diagnostic criterion of MDD. CONCLUSIONS: The study introduces the phenomenon of intuition into depression research. Additionally, these results extent findings from basic research showing that induced negative mood as well difficulties to down-regulate negative affect impair intuitive coherence judgments. Current results indicate that the negative affectivity of patients is the crucial mediator in the association between depression and impaired intuition. Limitations of the study as well as the potential etiological role of intuition in MDD are discussed. PRACTITIONER POINTS: The finding that intuition is impaired in depressed patients extends our knowledge as to the cognitive profile of patients with MDD. Patients who suffer from indecisiveness have lower intuition indices compared to patients who do not fulfill this diagnostic criterion of MDD. Due to the cross-sectional design, final conclusions as to the etiological role of intuition in MDD cannot be drawn. The question remains open whether impaired intuition is specific to MDD.

Telomere shortening in leukocyte subpopulations in depression.

BACKGROUND: Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes--as has been reported in depression--may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes). METHODS: Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH). RESULTS: Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years. CONCLUSIONS: A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations.

Medication adherence and cognitive performance in schizophrenia-spectrum and bipolar disorder: results from the PsyCourse Study.

Existing guidelines recommend psychopharmacological treatment for the management of schizophrenia and bipolar disorder as part of holistic treatment concepts. About half of the patients do not take their medication regularly, although treatment adherence can prevent exacerbations and re-hospitalizations. To date, the relationship between medication adherence and cognitive performance is understudied. Therefore, this study investigated the relationship between medication adherence and cognitive performance by analyzing the data of 862 participants with schizophrenia-spectrum and bipolar disorders (mean [SD] age, 41.9 [12.48] years; 44.8% female) from a multicenter study (PsyCourse Study). Z-scores for three cognitive domains were calculated, global functioning was measured with the Global Assessment of Functioning Scale, and adherence was assessed by a self-rating questionnaire. We evaluated four multiple linear regression models and built three clusters with hierarchical cluster analyses. Higher adherence behavior (p < 0.001) was associated with better global functioning but showed no impact on the cognitive domains learning and memory, executive function, and psychomotor speed. The hierarchical cluster analysis resulted in three clusters with different cognitive performances, but patients in all clusters showed similar adherence behavior. The study identified cognitive subgroups independent of diagnoses, but no differences were found in the adherence behavior of the patients in these new clusters. In summary, medication adherence was associated with global but not cognitive functioning in patients with schizophrenia-spectrum and bipolar disorders. In both diagnostic groups, cognitive function might be influenced by various factors but not medication adherence.

Prominent Efficacy of Amantadine against Human Borna Disease Virus Infection In Vitro and In Vivo. Comment on Fink et al. Amantadine Inhibits SARS-CoV-2 In Vitro. Viruses 2021, 13, 539.

Amantadine (1-amino-adamantane) is a versatile antiviral compound which has been licensed for decades against influenza viruses. During the Corona pandemic, its effect to inhibit SARS-CoV-2 in vitro has been investigated. However, an in vivo oral inapplicability was concluded due to ID50 doses exceeding eight times the estimated maximum tolerable plasma levels reached by 600 mg orally daily. In contrast, amantadine has been shown to be extraordinarily efficient against human neurotropic Borna disease virus (BoDV-1), presenting with both anti-depressive and anti-viral efficacy against a placebo, achieved by a well-tolerated low oral daily dose of 200 mg amantadine.

Hair cortisol level might be indicative for a 3PM approach towards suicide risk assessment in depression: comparative analysis of mentally stable and depressed individuals versus individuals after completing suicide.

Depression and suicidal behavior are interrelated, stress-associated mental health conditions, each lacking biological verifiability. Concepts of predictive, preventive, and personalized medicine (3PM) are almost completely missing for both conditions but are of utmost importance. Prior research reported altered levels of the stress hormone cortisol in the scalp hair of depressed individuals, however, data on hair cortisol levels (HCL) for suicide completers (SC) are missing. Here, we aimed to identify differences in HCL between subject with depression (n = 20), SC (n = 45) and mentally stable control subjects (n = 12) to establish the usage of HCL as a new target for 3PM. HCL was measured in extracts of pulverized hair (1-cm and 3-cm hair segments) using ELISA. In 3-cm hair segments, an average increase in HCL for depressed patients (1.66 times higher; p = .011) and SC (5.46 times higher; p = 1.65 × 10-5) compared to that for controls was observed. Furthermore, the average HCL in SC was significantly increased compared to that in the depressed group (3.28 times higher; p = 1.4 × 10-5). A significant correlation between HCL in the 1-cm and the 3-cm hair segments, as well as a significant association between the severity of depressive symptoms and HCL (3-cm segment) was found. To conclude, findings of increased HCL in subjects with depression compared to that in controls were replicated and an additional increase in HCL was seen in SC in comparison to patients with depression. The usage of HCL for creating effective patient stratification and predictive approach followed by the targeted prevention and personalization of medical services needs to be validated in follow-up studies.

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.

Reduced P300 and P600 amplitude in the hollow-mask illusion in patients with schizophrenia.

Illusions provide a useful tool to study the mechanisms by which top-down and bottom-up processes interact in perception. Patients suffering from schizophrenia are not as subject to the hollow-mask illusion as healthy controls, since studies have shown that controls perceive a hollow mask as a normal face, while patients with schizophrenia do not. This insusceptibility to the illusion is indicating a weakened top-down processing in schizophrenia and little is understood about the neurobiology of this phenomenon. We used event-related potentials to investigate the hollow-mask illusion in patients with schizophrenia and healthy controls. We hypothesized that there would be a visible reduction of top-down processing in the patients' group and that this reduction would occur in the late stages of processing. We found significantly decreased amplitudes in the P300 and P600 components in the patients' group, indicating that visual information does not benefit from frontal, parietal or temporal activity for perceiving incoming stimuli. We propose that a deficit in functional connectivity may be responsible for impaired top-down visual processing in schizophrenia. These data further the understanding of the time course of top-down processing in patients with schizophrenia.

Caution, "normal" BMI: health risks associated with potentially masked individual underweight-EPMA Position Paper 2021.

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters-all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice.

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.

Impaired top-down processes in schizophrenia: a DCM study of ERPs.

Perception is not simply based on a hierarchical organization of the brain; it arises from an interplay between inputs from the environment and internal predictions of these inputs. It is an active process which involves an interaction between bottom-up information coming from the senses and feedback connections coming from higher-order cortical areas. In our experiment, we use the hollow-mask illusion to investigate the strength of top-down processes in schizophrenic patients and healthy controls. By using dynamic causal modelling (DCM) on functional magnetic resonance tomography (fMRI) data, we have presented evidence to suggest that patients with schizophrenia are less constrained by top-down processes during perception (Dima, D., Roiser, J.P., Dietrich, D.E., Bonnemann, C., Lanfermann, H., Emrich, H.M., Dillo, W., 2009. Understanding why patients with schizophrenia do not perceive the hollow-mask illusion using dynamic causal modeling. Neuroimage 46, 1180-1186). In this study, we re-address this issue by using DCM on event-related potentials (ERPs) data. Our aim was to validate our previous findings by conducting the same connectivity analysis--DCM--on data obtained from a different neuroimaging method. Our results confirm our initial hypothesis that top-down influences are constrained in schizophrenia, especially in perceptual tasks that require top-down control, like the hollow-mask illusion.