Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses.

Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior.

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.

Stereological investigation of the posterior hippocampus in affective disorders.

Hippocampus volumes have been shown to be decreased in patients with major depression, but volume measurements are inconsistent in patients with bipolar disorder. Both disorders are associated with deficits in hippocampus-mediated cognitive functions. However, the underlying pathophysiology is widely unknown. In this post-mortem study, we used design-based stereology on Nissl-stained serial sections to investigate the number of neurons, oligodendrocytes and astrocytes in substructures of the posterior hippocampus in eight patients with major depression, eight patients with bipolar disorder and ten control patients without a neuropsychiatric disorder. Compared to controls, patients with bipolar disorder had significantly more neurons in the cornu ammonis subfield 1 (CA1) and the subiculum, while the number of oligodendrocytes was higher only in CA1. In patients with major depression, the density of oligodendrocytes was higher in CA2/3, CA4 and the subiculum. The dose of antidepressants correlated with the density and number of oligodendrocytes in CA2/3, indicating that antidepressants may affect our results. Treatment with neuroleptics expressed in chlorpromazine equivalents and benzodiazepines expressed in diazepam equivalents correlated negatively with the number of oligodendrocytes in CA2/3 and CA4, respectively, suggesting that treatment with these drugs do not influence cell number. We did not detect alterations in either volumes of substructures or numbers of astrocytes. Increased cell numbers argue for a denser packing of neurons and oligodendrocytes as a result of a decreased neuropils. This neuropathological process may be based on neurodevelopmental disturbances and may contribute to altered microconnectivity and cognitive deficits in affective disorders.

The effects of physical exercise in schizophrenia and affective disorders.

Affective and non-affective psychoses are severe and frequent psychiatric disorders. Amongst others, they not only have a profound impact on affected individuals through their symptomatology, but also regarding cognition, brain structure and function. Cognitive impairment influences patients' quality of life as well as their ability to work and being employed. While exercise therapy has been implemented in the treatment of psychiatric conditions since the days of Kraepelin and Bleuler, the underlying mechanisms have never been systematically studied. Since the early 1990s, studies emerged examining the effect of physical exercise in animal models, revealing stimulation of neurogenesis, synaptogenesis and neurotransmission. Based on that body of work, clinical studies have been carried out in both healthy humans and in patient populations. These studies differ with regard to homogenous study samples, sample size, type and duration of exercise, outcome variables and measurement techniques. Based on their review, we draw conclusions regarding recommendations for future research strategies showing that modern therapeutic approaches should include physical exercise as part of a multimodal intervention programme to improve psychopathology and cognitive symptoms in schizophrenia and affective disorders.

Association of early life stress and cognitive performance in patients with schizophrenia and healthy controls.

As core symptoms of schizophrenia, cognitive deficits contribute substantially to poor outcomes. Early life stress (ELS) can negatively affect cognition in patients with schizophrenia and healthy controls, but the exact nature of the mediating factors is unclear. Therefore, we investigated how ELS, education, and symptom burden are related to cognitive performance. The sample comprised 215 patients with schizophrenia (age, 42.9 ± 12.0 years; 66.0 % male) and 197 healthy controls (age, 38.5 ± 16.4 years; 39.3 % male) from the PsyCourse Study. ELS was assessed with the Childhood Trauma Screener (CTS). We used analyses of covariance and correlation analyses to investigate the association of total ELS load and ELS subtypes with cognitive performance. ELS was reported by 52.1 % of patients and 24.9 % of controls. Independent of ELS, cognitive performance on neuropsychological tests was lower in patients than controls (p < 0.001). ELS load was more closely associated with neurocognitive deficits (cognitive composite score) in controls (r = -0.305, p < 0.001) than in patients (r = -0.163, p = 0.033). Moreover, the higher the ELS load, the more cognitive deficits were found in controls (r = -0.200, p = 0.006), while in patients, this correlation was not significant after adjusting for PANSS. ELS load was more strongly associated with cognitive deficits in healthy controls than in patients. In patients, disease-related positive and negative symptoms may mask the effects of ELS-related cognitive deficits. ELS subtypes were associated with impairments in various cognitive domains. Cognitive deficits appear to be mediated through higher symptom burden and lower educational level.

Association between mitochondria-related genes and cognitive performance in the PsyCourse Study.

BACKGROUND: Mitochondria generate energy through oxidative phosphorylation (OXPHOS). The function of key OXPHOS proteins can be altered by variation in mitochondria-related genes, which may increase the risk of mental illness. We investigated the association of mitochondria-related genes and their genetic risk burden with cognitive performance. METHODS: We leveraged cross-sectional data from 1320 individuals with a severe psychiatric disorder and 466 neurotypical individuals from the PsyCourse Study. The cognitive tests analyzed were the Trail-Making Test, Verbal Digit Span Test, Digit-Symbol Test, and Multiple Choice Vocabulary Intelligence Test. Association analyses between the cognitive tests, and single-nucleotide polymorphisms (SNPs) mapped to mitochondria-related genes, and their polygenic risk score (PRS) for schizophrenia (SCZ) were performed with PLINK 1.9 and R program. RESULTS: We found a significant association (FDR-adjusted p < 0.05) in the Cytochrome C Oxidase Assembly Factor 8 (COA8) gene locus of the OXPHOS pathway with the Verbal Digit Span (forward) test. Mitochondrial PRS was not significantly associated with any of the cognitive tests. LIMITATIONS: Moderate statistical power due to relatively small sample size. CONCLUSIONS: COA8 encodes a poorly characterized mitochondrial protein involved in apoptosis. Here, this gene was associated with the Verbal Digit Span (forward) test, which evaluates short-term memory. Our results warrant replication and may lead to better understanding of cognitive impairment in mental disorders.

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.

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.

Concept of the Munich/Augsburg Consortium Precision in Mental Health for the German Center of Mental Health.

The Federal Ministry of Education and Research (BMBF) issued a call for a new nationwide research network on mental disorders, the German Center of Mental Health (DZPG). The Munich/Augsburg consortium was selected to participate as one of six partner sites with its concept "Precision in Mental Health (PriMe): Understanding, predicting, and preventing chronicity." PriMe bundles interdisciplinary research from the Ludwig-Maximilians-University (LMU), Technical University of Munich (TUM), University of Augsburg (UniA), Helmholtz Center Munich (HMGU), and Max Planck Institute of Psychiatry (MPIP) and has a focus on schizophrenia (SZ), bipolar disorder (BPD), and major depressive disorder (MDD). PriMe takes a longitudinal perspective on these three disorders from the at-risk stage to the first-episode, relapsing, and chronic stages. These disorders pose a major health burden because in up to 50% of patients they cause untreatable residual symptoms, which lead to early social and vocational disability, comorbidities, and excess mortality. PriMe aims at reducing mortality on different levels, e.g., reducing death by psychiatric and somatic comorbidities, and will approach this goal by addressing interdisciplinary and cross-sector approaches across the lifespan. PriMe aims to add a precision medicine framework to the DZPG that will propel deeper understanding, more accurate prediction, and personalized prevention to prevent disease chronicity and mortality across mental illnesses. This framework is structured along the translational chain and will be used by PriMe to innovate the preventive and therapeutic management of SZ, BPD, and MDD from rural to urban areas and from patients in early disease stages to patients with long-term disease courses. Research will build on platforms that include one on model systems, one on the identification and validation of predictive markers, one on the development of novel multimodal treatments, one on the regulation and strengthening of the uptake and dissemination of personalized treatments, and finally one on testing of the clinical effectiveness, utility, and scalability of such personalized treatments. In accordance with the translational chain, PriMe's expertise includes the ability to integrate understanding of bio-behavioral processes based on innovative models, to translate this knowledge into clinical practice and to promote user participation in mental health research and care.

Genetic risk for psychiatric illness is associated with the number of hospitalizations of bipolar disorder patients.

OBJECTIVES: Bipolar disorder (BD) has a highly heterogeneous clinical course that is characterized by relapses and increased health care utilization in a significant fraction of patients. A thorough understanding of factors influencing illness course is essential for predicting disorder severity and developing targeted therapies. METHODS: We performed polygenic score analyses in four cohorts (N = 954) to test whether the genetic risk for BD, schizophrenia, or major depression is associated with a severe course of BD. We analyzed BD patients with a minimum illness duration of five years. The severity of the disease course was assessed by using the number of hospitalizations in a mental health facility and a composite measure of longitudinal illness severity (OPCRIT item 90). RESULTS: Our analyses showed that higher polygenic scores for BD (ß = 0.11, SE = 0.03, p = 1.17 × 10-3) and schizophrenia (ß = 0.09, SE = 0.03, p = 4.24 × 10-3), but not for major depression, were associated with more hospitalizations. None of the investigated polygenic scores was associated with the composite measure of longitudinal illness severity (OPCRIT item 90). LIMITATIONS: We could not account for non-genetic influences on disease course. Our clinical sample contained more severe cases. CONCLUSIONS: This study demonstrates that the genetic risk burden for psychiatric illness is associated with increased health care utilization, a proxy for disease severity, in BD patients. The findings are in line with previous observations made for patients diagnosed with schizophrenia or major depression. Therefore, in the future psychiatric disorder polygenic scores might become helpful for stratifying patients with high risk of a chronic manifestation and predicting disease course.

Role of psychiatric hospitals during a pandemic: introducing the Munich Psychiatric COVID-19 Pandemic Contingency Plan.

BACKGROUND: Psychiatry is facing major challenges during the current coronavirus disease 2019 (COVID)-19 pandemic. These challenges involve its actual and perceived role within the medical system, in particular how psychiatric hospitals can maintain their core mission of attending to people with mental illness while at the same time providing relief to overstretched general medicine services. Although psychiatric disorders comprise the leading cause of the global burden of disease, mental healthcare has been deemphasised in the wake of the onslaught of the pandemic: to make room for emergency care, psychiatric wards have been downsized, clinics closed, psychiatric support systems discontinued and so on. To deal with this pressing issue, we developed a pandemic contingency plan with the aim to contain, decelerate and, preferably, avoid transmission of COVID-19 and to enable and maintain medical healthcare for patients with mental disorders. AIMS: To describe our plan as an example of how a psychiatric hospital can share in providing acute care in a healthcare system facing an acute and highly infectious pandemic like COVID-19 and at the same time provide support for people with mental illness, with or without a COVID-19 infection. METHOD: This was a descriptive study. RESULTS: The plan was based on the German national pandemic strategy and several legal recommendations and was implemented step by step on the basis of the local COVID-19 situation. In addition, mid- and long-term plans were developed for coping with the aftermath of the pandemic. CONCLUSIONS: The plan enabled the University Hospital to maintain medical healthcare for patients with mental disorders. It has offered the necessary flexibility to adapt its implementation to the first and second waves of the COVID-19 pandemic in Germany. The plan is designed to serve as an easily adaptable blueprint for psychiatric hospitals around the world.

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.