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.
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.
Cognitive deficits are a core feature of psychiatric disorders like schizophrenia and bipolar disorder. Evidence supports a genome-wide polygenic score (GPS) for educational attainment (GPS
) can be ...used to explain variability in cognitive performance. We aimed to identify different cognitive domains associated with GPS
in a transdiagnostic clinical cohort of chronic psychiatric patients with known cognitive deficits. Bipolar and schizophrenia patients from the PsyCourse cohort (N = 730; 43% female) were used. Likewise, we tested whether GPSs for schizophrenia (GPS
) and bipolar disorder (GPS
) were associated with cognitive outcomes. GPS
explained 1.5% of variance in the backward verbal digit span, 1.9% in the number of correctly recalled words of the Verbal Learning and Memory Test, and 1.1% in crystallized intelligence. These effects were robust to the influences of treatment and diagnosis. No significant associations between GPS
or GPS
with cognitive outcomes were found. Furthermore, these risk scores did not confound the effect of GPS
on cognitive outcomes. GPS
explains a small fraction of cognitive performance in adults with psychiatric disorders, specifically for domains related to linguistic learning and working memory. Investigating such a proxy-phenotype longitudinally, could give intriguing insight into the disease course, highlighting at what time genes play a more influential role on cognitive performance. Better understanding the origin of these deficits might help identify those patients at risk for lower levels of functioning and poor social outcomes. Polygenic estimates may in the future be part of predictive models for more personalized interventions.
Schizophrenia is the collective term for an exclusively clinically diagnosed, heterogeneous group of mental disorders with still obscure biological roots. Based on the assumption that valuable ...information about relevant genetic and environmental disease mechanisms can be obtained by association studies on patient cohorts of ≥ 1000 patients, if performed on detailed clinical datasets and quantifiable biological readouts, we generated a new schizophrenia data base, the GRAS (Göttingen Research Association for Schizophrenia) data collection. GRAS is the necessary ground to study genetic causes of the schizophrenic phenotype in a 'phenotype-based genetic association study' (PGAS). This approach is different from and complementary to the genome-wide association studies (GWAS) on schizophrenia.
For this purpose, 1085 patients were recruited between 2005 and 2010 by an invariable team of traveling investigators in a cross-sectional field study that comprised 23 German psychiatric hospitals. Additionally, chart records and discharge letters of all patients were collected.
The corresponding dataset extracted and presented in form of an overview here, comprises biographic information, disease history, medication including side effects, and results of comprehensive cross-sectional psychopathological, neuropsychological, and neurological examinations. With >3000 data points per schizophrenic subject, this data base of living patients, who are also accessible for follow-up studies, provides a wide-ranging and standardized phenotype characterization of as yet unprecedented detail.
The GRAS data base will serve as prerequisite for PGAS, a novel approach to better understanding 'the schizophrenias' through exploring the contribution of genetic variation to the schizophrenic phenotypes.
Identifying psychosis subgroups could improve clinical and research precision. Research has focused on symptom subgroups, but there is a need to consider a broader clinical spectrum, disentangle ...illness trajectories, and investigate genetic associations.
To detect psychosis subgroups using data-driven methods and examine their illness courses over 1.5 years and polygenic scores for schizophrenia, bipolar disorder, major depression disorder, and educational achievement.
This ongoing multisite, naturalistic, longitudinal (6-month intervals) cohort study began in January 2012 across 18 sites. Data from a referred sample of 1223 individuals (765 in the discovery sample and 458 in the validation sample) with DSM-IV diagnoses of schizophrenia, bipolar affective disorder (I/II), schizoaffective disorder, schizophreniform disorder, and brief psychotic disorder were collected from secondary and tertiary care sites. Discovery data were extracted in September 2016 and analyzed from November 2016 to January 2018, and prospective validation data were extracted in October 2018 and analyzed from January to May 2019.
A clinical battery of 188 variables measuring demographic characteristics, clinical history, symptoms, functioning, and cognition was decomposed using nonnegative matrix factorization clustering. Subtype-specific illness courses were compared with mixed models and polygenic scores with analysis of covariance. Supervised learning was used to replicate results in validation data with the most reliably discriminative 45 variables.
Of the 765 individuals in the discovery sample, 341 (44.6%) were women, and the mean (SD) age was 42.7 (12.9) years. Five subgroups were found and labeled as affective psychosis (n = 252), suicidal psychosis (n = 44), depressive psychosis (n = 131), high-functioning psychosis (n = 252), and severe psychosis (n = 86). Illness courses with significant quadratic interaction terms were found for psychosis symptoms (R2 = 0.41; 95% CI, 0.38-0.44), depression symptoms (R2 = 0.28; 95% CI, 0.25-0.32), global functioning (R2 = 0.16; 95% CI, 0.14-0.20), and quality of life (R2 = 0.20; 95% CI, 0.17-0.23). The depressive and severe psychosis subgroups exhibited the lowest functioning and quadratic illness courses with partial recovery followed by reoccurrence of severe illness. Differences were found for educational attainment polygenic scores (mean SD partial η2 = 0.014 0.003) but not for diagnostic polygenic risk. Results were largely replicated in the validation cohort.
Psychosis subgroups were detected with distinctive clinical signatures and illness courses and specificity for a nondiagnostic genetic marker. New data-driven clinical approaches are important for future psychosis taxonomies. The findings suggest a need to consider short-term to medium-term service provision to restore functioning in patients stratified into the depressive and severe psychosis subgroups.
Religious delusions are a common symptom in patients experiencing psychosis, with varying prevalence rates of religious delusions across cultures and societies. To enhance our knowledge of this ...distinct psychotic feature, we investigated the mutually-adjusted association of genetic and environmental factors with occurrence of religious delusions.
We studied 262 adult German patients with schizophrenia or schizoaffective disorder. Association with lifetime occurrence of religious delusions was tested by multiple logistic regression for the following putative predictors: self-reported degree of religious activity, DSM-IV diagnosis, sex, age, education level, marital status, presence of acute delusion at the time of interview and an individual polygenic schizophrenia-risk score (SZ-PRS, available in 239 subjects).
Of the 262 patients, 101 (39%) had experienced religious delusions. The risk of experiencing religious delusions was significantly increased in patients with strong religious activity compared to patients without religious affiliation (OR = 3.6, p = 0.010). Low or moderate religious activity had no significant effect. The same analysis including the SZ-PRS confirmed the effect of high religious activity on occurrence of religious delusions (OR = 4.1, p = 0.008). Additionally, the risk of experiencing religious delusions increased with higher SZ-PRS (OR 1.4, p = 0.020, using pT = 0.05 for SZ-PRS calculation). None of the other variables were significantly associated with lifetime occurrence of religious delusions.
Our results suggest that strong religious activity and high SZ-PRS are independent risk factors for the occurrence of religious delusions in schizophrenia and schizoaffective disorder.
Repetitive transcranial magnetic stimulation (rTMS) has been shown to be effective in the treatment of affective disorders. However, only little is known about hemodynamic physiological and safety ...aspects of this method. We studied the cerebral hemodynamics as measured by transcranial Doppler sonography in 20 healthy subjects during different rTMS procedures. Mean cerebral blood flow velocity (CBFV), pulsatility index (PI), and oxygen consumption were recorded continuously and averaged directly after the rTMS procedure. RTMS did not influence blood pressure, pulse rate, or blood oxygenation. There was a maximal increase of CBFV in the middle cererbal artery (MCA) of 3.6% and 5.6% during 10 Hz and 20 Hz stimulation, respectively. This increase was only seen on the stimulated left hemisphere. The PI remained unchanged during the whole procedure. It is likely that the increase of CBFV is due to dilatation of the small resistance vessels rather than due to vasoconstriction of the MCA. In terms of cerebral hemodynamics, rTMS is a safe and well-tolerated technique with a lower increase of CBFV than that seen in electroconvulsive therapy.
The question of how to define a therapeutically adequate electroconvulsive therapy (ECT) has been under discussion since the early days of ECT. Although convention has asserted a demand for minimum ...seizure times, the complex electrophysiological conditions involved in developing a generalized seizure make it problematic for therapeutic efficacy of ECT to be linked only with seizure duration. Within the framework of an open clinical study of 40 patients, selected parameters of the ictal electroencephalogram (EEG) have now been examined with respect to differentiation between therapeutically effective and ineffective treatments. For this purpose a rating scale covering both quantitative and qualitative features of the ictal EEG was used. Although this study recorded no correlations between seizure duration and clinical improvement, correlations were established between clinical improvement, on the one hand, and the frequency of epileptic discharges and their slowing during the spike-wave phase as well as the stereotypy of the discharge or a "stable" pattern of rhythmic spike-wave or sharp wave complexes, on the other. The results suggest that several of these EEG parameters might be combined to form a marker for therapeutically adequate ECT, and that treatment might be controlled accordingly.
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