Open Access

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.

Vitamin deficiency syndromes and blood–brain barrier (BBB) dysfunction are frequent phenomena in psychiatric conditions. We analysed the largest available first-episode schizophrenia-spectrum psychosis (FEP) cohort to date regarding routine cerebrospinal fluid (CSF) and blood parameters to investigate the association between vitamin deficiencies (vitamin B12 and folate) and BBB impairments in FEP. We report a retrospective analysis of clinical data from all inpatients that were admitted to our tertiary care hospital with an ICD-10 diagnosis of a first-episode F2x (schizophrenia-spectrum) between January 1, 2008 and August 1, 2018 and underwent a lumbar puncture, blood-based vitamin status diagnostics and neuroimaging within the clinical routine. 222 FEP patients were included in our analyses. We report an increased CSF/serum albumin quotient (Qalb) as a sign of BBB dysfunction in 17.1% (38/222) of patients. White matter lesions (WML) were present in 29.3% of patients (62/212). 17.6% of patients (39/222) showed either decreased vitamin B12 levels or decreased folate levels. No statistically significant association was found between vitamin deficiencies and altered Qalb. This retrospective analysis contributes to the discussion on the impact of vitamin deficiency syndromes in FEP. Although decreased vitamin B12 or folate levels were found in approximately 17% of our cohort, we found no evidence for significant associations between BBB dysfunction and vitamin deficiencies. To strengthen the evidence regarding the clinical implications of vitamin deficiencies in FEP, prospective studies with standardized measurements of vitamin levels together with follow-up measurements and assessment of symptom severity in addition to CSF diagnostics are needed.

Introduction: Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. Methods: In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Results: Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. Discussion: The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

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 implementation status of clinical guidelines is, despite their important role in connecting research with practice, frequently not satisfactory. This study aims to investigate the implementation status of the current German guideline for schizophrenia. Moreover, the attitude toward a living guideline has been explored for the first time by presenting screenshots of the German schizophrenia guideline transferred to a digital living guideline format called MAGICapp. A cross-sectional online survey was performed under the participation of 17 hospitals for psychiatry and psychosomatic medicine in Southern Germany and one professional association for German neurologists and psychiatrists. 439 participants supplied sufficient data for analysis. 309 provided complete data sets. Regarding the current guideline for schizophrenia and key recommendations, a large awareness-to-adherence gap was found. Group comparisons between different professions (caregivers, medical doctors, psychologists/psychotherapists, psychosocial therapists) detected differences in the implementation status showing higher awareness and agreement with the schizophrenia guideline and its key recommendations among medical doctors compared to psychosocial therapists and caregivers. Moreover, we detected differences in the implementation status of the guideline as a whole and its key recommendations between specialist and assistant doctors. The attitude toward an upcoming living guideline was mostly positive, especially among younger healthcare professionals. Our findings confirm an awareness-to-adherence gap, not only for the current schizophrenia guideline in general but also for its key recommendations with apparent differences between professions. Overall, our results show promising positive attitudes toward the living guideline for schizophrenia among healthcare providers, suggesting that a living guideline may be a supportive tool in everyday clinical practice.

Background Quick symptomatic remission after the onset of psychotic symptoms is critical in schizophrenia treatment, determining the subsequent disease course and recovery. In this context, only every second patient with acute schizophrenia achieves symptomatic remission within three months of initiating antipsychotic treatment. The potential indication extension of clozapine—the most effective antipsychotic—to be introduced at an earlier stage (before treatment-resistance) is supported by several lines of evidence, but respective clinical trials are lacking. Methods Two hundred-twenty patients with acute non-treatment-resistant schizophrenia will be randomized in this double-blind, 8-week parallel-group multicentric trial to either clozapine or olanzapine. The primary endpoint is the number of patients in symptomatic remission at the end of week 8 according to international consensus criteria (‘Andreasen criteria’). Secondary endpoints and other assessments comprise a comprehensive safety assessment (i. e., myocarditis screening), changes in psychopathology, global functioning, cognition, affective symptoms and quality of life, and patients’ and relatives’ views on treatment. Discussion This multicentre trial aims to examine whether clozapine is more effective than a highly effective second-generation antipsychotics (SGAs), olanzapine, in acute schizophrenia patients who do not meet the criteria for treatment-naïve or treatment-resistant schizophrenia. Increasing the likelihood to achieve symptomatic remission in acute schizophrenia can improve the overall outcome, reduce disease-associated burden and potentially prevent mid- and long-term disease chronicity.

This study aims to investigate the barriers and facilitators to guideline adherence for the print format of the German schizophrenia guideline as well as for the concept of a digital living guideline for the first time. For this purpose, the schizophrenia guideline was transferred to a digital guideline format within the web-based tool MAGICapp. An online survey was performed under participation of mental healthcare professionals (medical doctors, psychologists/psychotherapists, psychosocial therapists, caregivers) in 17 hospitals for psychiatry in Southern Germany and a professional association for German neurologists and psychiatrists. 524 participants opened the survey, 439 completed the demographic questions and commenced the content-related survey and 309 provided complete data sets. Results indicate a higher occurrence of knowledge-related barriers for the living guideline. The print version is associated with more attitude-related and external barriers. Older professionals reported more attitude-related barriers to a living guideline compared to younger professionals. Differences between professions regarding barriers were found for both formats. Various barriers exist for both guideline formats and a need for facilitators was expressed across professions. Many of the mentioned obstacles and facilitators can be more easily addressed with living guidelines. However, also living guidelines face barriers. Thus, the introduction of these new formats alone cannot lead to sustainable behavior change regarding guideline adherence. Yet, living guidelines seem to be a cornerstone to improved and tailored guideline implementation as they facilitate to keep recommendations up to date and to address the need of individual professional groups.

Background and Hypothesis Cognitive impairment is a hallmark of schizophrenia, but no effective treatment is available to date. The underlying pathophysiology includes disconnectivity between hippocampal and prefrontal brain regions. Supporting evidence comes from diffusion-weighted imaging studies that suggest abnormal organization of frontotemporal white matter pathways in schizophrenia. Study Design Here, we hypothesize that in schizophrenia, deficient maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes substantially contributes to abnormal frontotemporal macro- and micro-connectivity and subsequent cognitive deficits. Study Results Our postmortem studies indicate a reduced oligodendrocyte number in the cornu ammonis 4 (CA4) subregion of the hippocampus, and others have reported the same histopathological finding in the dorsolateral prefrontal cortex. Our series of studies on aerobic exercise training showed a volume increase in the hippocampus, specifically in the CA4 region, and improved cognition in individuals with schizophrenia. The cognitive effects were subsequently confirmed by meta-analyses. Cell-specific schizophrenia polygenic risk scores showed that exercise-induced CA4 volume increase significantly correlates with OPCs. From animal models, it is evident that early life stress and oligodendrocyte-related gene variants lead to schizophrenia-related behavior, cognitive deficits, impaired oligodendrocyte maturation, and reduced myelin thickness. Conclusions Based on these findings, we propose that pro-myelinating drugs (e.g., the histamine blocker clemastine) combined with aerobic exercise training may foster the regeneration of myelin plasticity as a basis for restoring frontotemporal connectivity and cognition in schizophrenia.

Cognitive deficits are a core symptom of schizophrenia, but research on their neural underpinnings has been challenged by the heterogeneity in deficits’ severity among patients. Here, we address this issue by combining logistic regression and random forest to classify two neuropsychological profiles of patients with high (HighCog) and low (LowCog) cognitive performance in two independent samples. We based our analysis on the cortical features grey matter volume (VOL), cortical thickness (CT), and mean curvature (MC) of N = 57 patients (discovery sample) and validated the classification in an independent sample (N = 52). We investigated which cortical feature would yield the best classification results and expected that the 10 most important features would include frontal and temporal brain regions. The model based on MC had the best performance with area under the curve (AUC) values of 76% and 73%, and identified fronto-temporal and occipital brain regions as the most important features for the classification. Moreover, subsequent comparison analyses could reveal significant differences in MC of single brain regions between the two cognitive profiles. The present study suggests MC as a promising neuroanatomical parameter for characterizing schizophrenia cognitive subtypes.

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing.

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.