Schizophrenia is a severe neuropsychiatric disorder with persistence of symptoms throughout adult life in most of the affected patients. This unfavorable course is associated with multiple episodes ...and residual symptoms, mainly negative symptoms and cognitive deficits. The neural diathesis-stress model proposes that psychosocial stress acts on a pre-existing vulnerability and thus triggers the symptoms of schizophrenia. Childhood trauma is a severe form of stress that renders individuals more vulnerable to developing schizophrenia; neurobiological effects of such trauma on the endocrine system and epigenetic mechanisms are discussed. Childhood trauma is associated with impaired working memory, executive function, verbal learning, and attention in schizophrenia patients, including those at ultra-high risk to develop psychosis. In these patients, higher levels of childhood trauma were correlated with higher levels of attenuated positive symptoms, general symptoms, and depressive symptoms; lower levels of global functioning; and poorer cognitive performance in visual episodic memory end executive functions. In this review, we discuss effects of specific gene variants that interact with childhood trauma in patients with schizophrenia and describe new findings on the brain structural and functional level. Additive effects between childhood trauma and brain-derived neurotrophic factor methionine carriers on volume loss of the hippocampal subregions cornu ammonis (CA)4/dentate gyrus and CA2/3 have been reported in schizophrenia patients. A functional magnetic resonance imaging study showed that childhood trauma exposure resulted in aberrant function of parietal areas involved in working memory and of visual cortical areas involved in attention. In a theory of mind task reflecting social cognition, childhood trauma was associated with activation of the posterior cingulate gyrus, precuneus, and dorsomedial prefrontal cortex in patients with schizophrenia. In addition, decreased connectivity was shown between the posterior cingulate/precuneus region and the amygdala in patients with high levels of physical neglect and sexual abuse during childhood, suggesting that disturbances in specific brain networks underlie cognitive abilities. Finally, we discuss some of the questionnaires that are commonly used to assess childhood trauma and outline possibilities to use recent biostatistical methods, such as machine learning, to analyze the resulting datasets.
Although the mood stabilizer lithium is a first-line treatment in bipolar disorder, a substantial number of patients do not benefit from it and experience side effects. No clinical tool is available ...for predicting lithium response or the occurrence of side effects in everyday clinical practice. Multiple genetic research efforts have been performed in this field because lithium response and side effects are considered to be multifactorial endophenotypes. Available results from linkage and segregation, candidate-gene, and genome-wide association studies indicate a role of genetic factors in determining response and side effects. For example, candidate-gene studies often report GSK3β, brain-derived neurotrophic factor, and SLC6A4 as being involved in lithium response, and the latest genome-wide association study found a genome-wide significant association of treatment response with a locus on chromosome 21 coding for two long non-coding RNAs. Although research results are promising, they are limited mainly by a lack of replicability and, despite the collaboration of consortia, insufficient sample sizes. The need for larger sample sizes and "multi-omics" approaches is apparent, and such approaches are crucial for choosing the best treatment options for patients with bipolar disorder. In this article, we delineate the mechanisms of action of lithium and summarize the results of genetic research on lithium response and side effects.
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.
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.
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.
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).
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.
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.
•Early life stress is often reported by patients with schizophrenia (52.1%) and healthy controls (24.9%).•Early life stress is more strongly associated with neurocognitive deficits in controls than in patients with schizophrenia.•The higher the early life stress load, the more symptoms and cognitive deficits are found.•Disease-related symptoms may mask the effects of early life stress-related cognitive deficits in patients with schizophrenia.•Cognitive deficits appear to be mediated through higher symptom burden and lower educational level.
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.
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.
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.
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.
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.
Major depression is one of the most common psychiatric disorders with a high rate of treatment resistance where new treatment options are urgently warranted. One of these new options are non-invasive ...brain stimulation techniques like transcranial magnetic or electric stimulation. One of the latter is transcranial Alternating Current Stimulation (tACS) in various frequencies. Here, we report a case series of six patients suffering from major depression treated with tACS in gamma (40 Hz) frequency. Patients were randomized to two groups, receiving either two 10-min stimulations (group 1) or a 20-min stimulation or per day (group 2) over ten days. Hamilton Depression Rating Scale and Beck Depression Inventory decreased during treatment in both study groups by 85% and 78% (group 1), or 62% and 24% respectively (group 2). Results also showed an improvement in cognitive functions assessed by word fluency and n-back test. It is hypothesized that gamma tACS could help to synchronize disturbed frequency bands in frontal and prefrontal cortex areas and thus restore dysbalanced neural connectivity in psychiatric disorders.
Zusammenfassung
Hintergrund
Forschung an Menschen im Freiheitsentzug wirft schwerwiegende Fragen auf. Dies gilt insbesondere für verhaltensgenetische Studien.
Fragestellung
Bringt der Einschluss ...forensisch-psychiatrisch Untergebrachter in genetische Studien einen Erkenntnisgewinn und ist aus ethischer und juristischer Sicht grundsätzlich vertretbar?
Methode
Auswertung vorhandener Literatur und interdisziplinäre Reflexion.
Ergebnisse
Ausgehend von forschungsethischen Prinzipien und rechtlichen Normen werden zunächst Nutzen und Gefahren solcher Forschungsvorhaben unter Berücksichtigung der besonderen Situation von Proband:innen im Freiheitsentzug bedacht. Die grundrechtlich verbürgte Forschungsfreiheit rechtfertigt auch in der forensischen Psychiatrie und Psychotherapie Grundlagenforschung. Deren möglicher Nutzen durch zukünftig verbesserte Behandlung ist vor allem gegenüber potenziellen Datenlecks und den aus einer unsachgerechten öffentlichen Rezeption von Forschungsergebnissen resultierenden Risiken abzuwägen. Mögliche Gefährdungen der freiwilligen und informierten Einwilligung in die Studienteilnahme werden im Lichte des ethischen Konzepts der Vulnerabilitäten genauer analysiert und Empfehlungen für eine vertretbare Umsetzung gegeben.
Schlussfolgerungen
Der Einschluss forensisch untergebrachter Proband:innen kann aus ethischer und rechtlicher Sicht dadurch gerechtfertigt werden, die selbstbestimmte Einwilligung durch besondere organisatorische und verfahrensrechtliche Maßnahmen abzusichern, beispielsweise durch eine klare personelle und organisatorische Trennung von Vollzug und Forschung.
Despite numerous mobile health (mHealth) applications available, current impact on mental healthcare is low. Users face overwhelming variety of applications and sensors. Evidence for distinct ...features' effectiveness is largely lacking. Along with technical feasibility and data security issues, readiness and preferences of patients predetermine engagement and impact of mHealth in psychiatry.
We aimed to assess the prospective attitudes of psychiatric patients and mental health professionals (MHP) towards mHealth applications in general and with regard to distinct features.
We conducted a survey entailing 486 subjects (297 MHP and 189 patients).
Professionals and patients indicate both, considerable acceptance and rejection for most features. Marked concerns across groups relate to data security in general. Actimetry and geotracking were considered particularly skeptical. Importantly, most patients prefer to be prompted timely about health status changes.
Altogether, evidence indicates substantial support for mHealth features in mental healthcare despite considerable rejection of distinct features. We conclude that tighter collaboration between researchers, developers and clinicians must address matching mHealth-apps to patients' needs. Improved information on potential risks and possibilities associated with mHealth features is strongly indicated in MHP and psychiatric patients in order to reach an appropriately informed decision on individual involvement.
Both common and rare genetic factors involved in increasing an individual's risk for schizophrenia (SCZ) have been identified in population-scale studies. Yet, little is known about how these ...translate at the individual level and what functional consequences they entail. Recent advances in the analysis strategies of RNA-Seq data are beginning to place whole transcriptome analyses (WTA) on the same playing field as whole exome sequencing when it comes to the identification of genetic variants at an individual level. In rare monogenic disorders, WTA have been used to identify genetic causes at an individual level and to interpret the functional consequences of the identified variants via expression or splicing outliers (e.g. Kremer L et al., Nat Commun, 2017; Cummings BB et al., Sci Transl Med, 2017; Gonorazky HD et al., Am J Hum Genet, 2019). However, little is known about how these strategies translate to common, complex genetic disorders like SCZ.
Transcriptomes from whole blood were sequenced for a total of 538 individuals with a DSM-IV SCZ-spectrum diagnosis belonging to the naturalistic, longitudinal, deep-phenotyping PsyCourse Study, recruited across Germany and Austria. For RNA-Seq, Lexogene QuantSeq was employed on an Illumina platform. Expression and splicing outliers in the full dataset were established using OUTRIDER and FRASER2 as implemented in the DROP workflow (Yepez VA, et al. Nat Protoc, 2021). Results were filtered against known high-confidence GWAS genes (n=130), rare variant association study (RVAS) genes (n=61), and genes within eight known SCZ-linked copy number variants (CNVs, n=326).
After quality control, 44 out of 534 individuals (8.2%) had expression outliers (z-score > 5.0) in at least one of the GWAS, RVAS, or CNV genes expressed in blood. In 10 individuals (1.9%), more than one GWAS, RVAS, or CNV gene proved to be an expression outlier. 2.4% of individuals had at least one CNV gene affected by an expression outlier in chr22q11, chr16p11, chr3q29 or chr7q11 and in 0.6% of individuals more than one gene in close proximity in the same CNV region showed aberrant expression, suggesting the yet unknown presence of the respective CNV in that individual. Splicing outliers in at least one GWAS, RVAS, or CNV gene were present in 10 individuals (1.9%), with three genes (SRRM2, TMEM219, and PDE4B) showing aberrant splicing affecting the same splice sites in more than one individual. Correlation with deep phenotypic meta data as well as proteomic and lipidomic data from the same individuals is underway and will be presented at the meeting.
Expression and splicing outliers can be detected in a naturalistic sample of individuals with SCZ using the same methodologies employed for the detection of rare aberrant expression and splicing events due to rare genetic variants in monogenic disorders. It highlights the fact that functional consequences of rare variants in SCZ-related genes are reflected in the periphery. It further suggests the presence of previously undiagnosed CNVs in some individuals in at least 0.6% of individuals, alluding to its potential to be explored as a possible diagnostic application. Analysis of larger sample sets including healthy controls using the same methodology would also allow to integrate direct functional annotations into RVAS, thus potentially increasing their power to detect biologically meaningful signals.
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