Open Access

Background Even before the onset of psychotic symptoms, individuals with schizophrenia display cognitive impairments. Simultaneously, increasing amounts of individuals exhibit dysfunction of the blood–brain barrier (BBB). However, the impact of BBB dysfunction on neurocognitive impairment in people with first-episode psychosis has not yet been investigated. Aims To advance understanding of said relationship, we considered one of the largest first-episode psychosis cohorts with cerebrospinal fluid parameters available, and investigated whether BBB dysfunction is related to working memory, working speed and attention. Method We conducted a retrospective chart review of 121 in-patients diagnosed with a first episode of a schizophrenia spectrum disorder. Patients underwent neurocognitive testing and a lumbar puncture within routine clinical care. To define BBB dysfunction, albumin cerebrospinal fluid/serum quotients, immunoglobulin G ratios and oligoclonal band types were evaluated, and gender-specific differences investigated. Neurocognitive functioning was assessed by the Wechsler Adult Intelligence Scale, Test of Attentional Performance and Repeatable Battery for the Assessment of Neuropsychological Status. We performed simple and multiple linear regression analyses to interpret associations of interest. Results Of those tested, 16% showed an alteration in albumin quotients and 12% had an oligoclonal band type indicating BBB dysfunction. Notably, male patients were more likely to have an increased albumin quotient and a higher immunoglobulin G ratio than female patients. We found no significant association between BBB dysfunction and neurocognitive assessments. Conclusions The hypothesised relationship between BBB and neurocognitive impairments was not detectable in our retrospective cohort. Further cerebrospinal fluid-based studies with a longitudinal assessment of cognitive functioning and disease trajectory are urgently needed.

Background Clinical practice guidelines are crucial for enhancing healthcare quality and patient outcomes. Yet, their implementation remains inconsistent across various professions and disciplines. Previous findings on the implementation of the German guideline for schizophrenia (2019) revealed low adherence rates among healthcare professionals. Barriers to guideline adherence are multifaceted, influenced by individual, contextual, and guideline-related factors. This study aims to investigate the effectiveness of a digital guideline version compared to print/PDF formats in enhancing guideline adherence. Methods A multicenter, cluster-randomized controlled trial was conducted in South Bavaria, Germany, involving psychologists and physicians. Participants were divided into two groups: implementation of the guideline using a digital online version via the MAGICapp platform and the other using the traditional print/PDF version. The study included a baseline assessment and a post-intervention assessment following a 6-month intervention phase. The primary outcome was guideline knowledge, which was assessed using a guideline knowledge questionnaire. Results The study included 217 participants at baseline and 120 at post-intervention. Both groups showed significant improvements in guideline knowledge; however, no notable difference was found between both study groups regarding guideline knowledge at either time points. At baseline, 43.6% in the control group (CG) and 52.5% of the interventional group (IG) met the criterion. There was no significant difference in the primary outcome between the two groups at either time point (T0: Chi2(1) = 1.65, p = 0.199, T1: Chi2(1) = 0.34, p = 0.561). At post-intervention, both groups improved, with 58.2% in the CG and 63.5% in the IG meeting this criterion. Conclusions While the study did not include a control group without any implementation strategy, the overall improvement in guideline knowledge following an implementation strategy, independent of the format, was confirmed. The digital guideline version, while not superior in enhancing knowledge, showed potential benefits in shared decision-making skills. However, familiarity with traditional formats and various barriers to digital application may have influenced these results. The study highlights the importance of tailored implementation strategies, especially for younger healthcare providers.

Background If people with episodic mental-health conditions lose their job due to an episode of their mental illness, they often experience personal negative consequences. Therefore, reintegration after sick leave is critical to avoid unfavorable courses of disease, longer inability to work, long payment of sickness benefits, and unemployment. Existing return-to-work (RTW) programs have mainly focused on “common mental disorders” and often used very elaborate and costly interventions without yielding convincing effects. It was the aim of the RETURN study to evaluate an easy-to-implement RTW intervention specifically addressing persons with mental illnesses being so severe that they require inpatient treatment. Methods The RETURN study was a multi-center, cluster-randomized controlled trial in acute psychiatric wards addressing inpatients suffering from a psychiatric disorder. In intervention wards, case managers (RTW experts) were introduced who supported patients in their RTW process, while in control wards treatment, as usual, was continued. Results A total of 268 patients were recruited for the trial. Patients in the intervention group had more often returned to their workplace at 6 and 12 months, which was also mirrored in more days at work. These group differences were statistically significant at 6 months. However, for the main outcome (days at work at 12 months), differences were no longer statistically significant (p = 0.14). Intervention patients returned to their workplace earlier than patients in the control group (p = 0.040). Conclusions The RETURN intervention has shown the potential of case-management interventions when addressing RTW. Further analyses, especially the qualitative ones, may help to better understand limitations and potential areas for improvement.

Background Refugees and asylum seekers (RAS) in Germany need tailored and resource-oriented mental healthcare interventions. Aims To evaluate the cost-effectiveness of group psychotherapy for RAS with moderate depressive symptoms. Method This is a post hoc cost-effectiveness analysis of Empowerment group psychotherapy that was embedded in a stratified stepped and collaborative care model (SCCM) from the multicentre randomised controlled MEHIRA trial. One hundred and forty-nine participants were randomly assigned to SCCM or treatment as usual (TAU) and underwent Empowerment (i.e. level 3 of the SCCM for adults) or TAU. Effects were measured with the nine-item Patient Health Questionnaire (PHQ-9) and quality adjusted life-years (QALY) post-intervention. Health service and intervention costs were measured. Incremental cost-effectiveness ratios (ICER) were estimated and net monetary benefit (NMB) regressions with 95% confidence intervals were performed. Cost-effectiveness was ascertained for different values of willingness to pay (WTP) using cost-effectiveness acceptability curves for probable scenarios. Trial registration number: NCT03109028 on ClinicalTrials.gov. Results Health service use costs were significantly lower for Empowerment than TAU after 1 year. Intervention costs were on average €409.6. Empowerment led to a significant change in PHQ-9 scores but not QALY. Bootstrapped mean ICER indicated cost-effectiveness according to PHQ-9 and varied considerably for QALY in the base case. NMB for a unit reduction in PHQ-9 score at WTP of €0 was €354.3 (€978.5 to −€269.9). Results were confirmed for different scenarios and varying WTP thresholds. Conclusions The Empowerment intervention was cost-effective in refugees with moderate depressive symptoms regarding the clinical outcome and led to a reduction in direct healthcare consumption. Concerning QALYs, there was a lack of confidence that Empowerment differed from TAU.

The blood-cerebrospinal fluid barrier (BCB) is impaired in a substantial proportion of individuals with schizophrenia-spectrum disorders (SSD). Even though disruption of the BCB is associated with higher symptom severity, factors linked to BCB disruption in SSDs have been minimally investigated. To address this gap, 57 inpatients with SSD underwent cerebrospinal fluid (CSF), blood analyses, and comprehensive clinical assessments. In a subgroup of 28 participants, structural magnetic resonance imaging (MRI) was performed. We developed a BCB dysfunction score, employing principal component analysis of CSF/serum albumin, CSF/serum IgG ratios, and total protein levels in CSF, with higher values indicating stronger abnormalities. Bayesian linear and logistic regression models were calculated to explore the associations between BCB integrity and cardiometabolic, inflammatory, cerebroventricular, and clinical measures. Our results indicated very strong evidence for a negative association between the BCB dysfunction score and high-density lipoprotein cholesterol, as well as extreme evidence for positive associations between the BCB dysfunction score and total, low-density lipoprotein cholesterol, and triglycerides. Furthermore, there was moderate evidence of a positive association between BCB dysfunction score and treatment resistance. We did not find evidence of associations between the BCB composite score and any other assessed cardiometabolic, inflammatory, or cerebroventricular measures. These findings suggest that BCB integrity is associated with dyslipidemia and treatment resistance in SSD, highlighting the interplay between cardiometabolic risk factors and brain health in SSD. Addressing cardiometabolic health in individuals with SSD could influence the integrity of the BCB and, consequently, clinical trajectories.

Background: Promoting social inclusion is crucial for people living with severe mental illness (SMI), who often experience high levels of social exclusion. However, research that uses a psychometric social inclusion measure to identify factors that determine varying levels of social inclusion in individuals with SMI is scarce. Aims: This study aimed to examine to what extent people with SMI feel socially included and to identify factors associated with perceived social inclusion among people with SMI. Method: A cross-sectional multicenter investigation of psychiatric inpatients and day hospital patients with SMI aged 18 to 65 years (n = 358) was conducted. Perceived social inclusion, sociodemographic, and clinical characteristics were assessed using the Measure of Participation and Social Inclusion for Use in People with a Chronic Mental Disorder (F-INK). Hierarchical multiple linear regression was performed to analyse the association between social inclusion and potential predictors. Results: The participants' overall level of social inclusion was moderate (F-INK social inclusion total score M = 1.9, SD = 0.6). Age, relationship status, diagnostic group, employment status, and living situation emerged as predictors of social inclusion. Greater subjective social inclusion was predicted by older age (p = .027), being in a committed intimate relationship (p = .037), diagnosis of schizophrenia spectrum disorder (compared to diagnosis of depression, p = .020), being competitively employed or in education (compared to being in sheltered employment, p = .022; compared to being unemployed or receiving a disability pension, p = .007), and living with other people (p = .042). Conclusions: The results confirm deficiencies in social inclusion of people with SMI. Individuals with SMI who are younger, single, have a diagnosis of depression, are in sheltered employment, are unemployed or receiving a disability pension, and are living alone seem to be particularly at risk of experiencing low social inclusion. These findings highlight the importance of psychosocial interventions in rehabilitative mental healthcare.

Exercise interventions are nowadays considered as effective add-on treatments in people with schizophrenia but are usually associated with high dropout rates. Therefore, the present study investigated potential predictors of adherence from a large multicenter study, encompassing two types of exercise training, conducted over a 6-month period with individuals with schizophrenia. First, we examined the role of multiple participants’ characteristics, including levels of functioning, symptom severity, cognitive performance, quality of life, and physical fitness. Second, we used K-means clustering to identify clinical subgroups of participants that potentially exhibited superior adherence. Last, we explored if adherence could be predicted on the individual level using Random Forest, Logistic Regression, and Ridge Regression. We found that individuals with higher levels of functioning at baseline were more likely to adhere to the exercise interventions, while other factors such as symptom severity, cognitive performance, quality of life or physical fitness seemed to be less influential. Accordingly, the high-functioning group with low symptoms exhibited a greater likelihood of adhering to the interventions compared to the severely ill group. Despite incorporating various algorithms, it was not possible to predict adherence at the individual level. These findings add to the understanding of the factors that influence adherence to exercise interventions. They underscore the predictive importance of daily life functioning while indicating a lack of association between symptom severity and adherence. Future research should focus on developing targeted strategies to improve adherence, particularly for people with schizophrenia who suffer from impairments in daily functioning.

BackgroundEndurance exercise in general and marathon running in particular have become increasingly popular over the past decades. Recent investigations about personality structures in this cohort and comparisons to non-active cohorts are lacking. MethodsIn the ReCaP study (Running effects on Cognition and Plasticity), a total of 100 marathon runners and 46 sedentary controls were recruited. After elimination of Minnesota Multiphasic Personality Inventory 2 Restructured Form (MMPI-2-RF) profiles with insufficient validity, 79 marathon runners (MA) and 27 sedentary controls (SC) remained for final analyses. Depressive symptoms were evaluated with Beck Depression Inventory (BDI) and Hamilton Depression Scale (HAMD). ResultsMarathon runners had lower scores in scales measuring somatic and cognitive complaints, stress, demoralization, hopelessness and distrust. Within the marathon group, committed runners exhibited hypomanic traits compared to regular runners. Discussion and ConclusionPersonality differences could be summarized as (sub-)depressive personality traits in SC compared to MA rather than typical (sub-) depressive symptoms in the meaning of depressive disorders. Future studies should further evaluate cause and consequence of endurance training and hypomanic or euthymic symptoms, as a two-way interaction exists. Trial Registrationhttp://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00012496.

Cognitive symptoms are a core feature of schizophrenia and are related to an unfavorable disease outcome. So far, there are no satisfactory pharmacological approaches to address cognitive symptoms. For some time now, aerobic exercise has been demonstrated in various trials to be a promising candidate for this indication. The aim of this brief qualitative review was to present the most recent meta-analyses regarding the capacity of exercise to improve cognition in schizophrenia patients. Additionally, we give a short overview of the effects in other conditions, like healthy subjects and patients with major depression. We conducted a focused literature search using the PubMed database, concentrating on meta-analyses which are based on a systematic search. The most recent meta-analysis investigating the efficacy of aerobic exercise on cognitive impairments in schizophrenia patients provides evidence that exercise has positive effects on cognitive functioning in this population. However, the effect seems not to be specific; there were positive findings regarding healthy subjects and patients with depressive disorders as well, even if they were less consistent. As most available trials have a small to modest sample size and have no consensus with regard to the intervention regime, nor to the assessment of cognition, the findings are difficult to generalize. In the future, standardized clinical trials focusing on the long-term effects of exercise are needed to evaluate whether the improvements in cognition are sustainable.


The response variability to repetitive transcranial magnetic stimulation (rTMS) challenges the effective use of this treatment option in patients with schizophrenia. This variability may be deciphered by leveraging predictive information in structural MRI, clinical, sociodemographic, and genetic data using artificial intelligence. We developed and cross-validated rTMS response prediction models in patients with schizophrenia drawn from the multisite RESIS trial. The models incorporated pre-treatment sMRI, clinical, sociodemographic, and polygenic risk score (PRS) data. Patients were randomly assigned to receive active (N = 45) or sham (N = 47) rTMS treatment. The prediction target was individual response, defined as ≥20% reduction in pre-treatment negative symptom sum scores of the Positive and Negative Syndrome Scale. Our multimodal sequential prediction workflow achieved a balanced accuracy (BAC) of 94% (non-responders: 92%, responders: 95%) in the active-treated group and 50% in the sham-treated group. The clinical, clinical + PRS, and sMRI-based classifiers yielded BACs of 65%, 76%, and 80%, respectively. Apparent sadness, inability to feel, educational attainment PRS, and unemployment were most predictive of non-response in the clinical + PRS model, while grey matter density reductions in the default mode, limbic networks, and the cerebellum were most predictive in the sMRI model. Our sequential modelling approach provided superior predictive performance while minimising the diagnostic burden in the clinical setting. Predictive patterns suggest that rTMS responders may have higher levels of brain grey matter in the default mode and salience networks which increases their likelihood of profiting from plasticity-inducing brain stimulation methods, such as rTMS. The future clinical implementation of our models requires findings to be replicated at the international scale using stratified clinical trial designs.