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.

Neuroinflammation and blood-cerebrospinal fluid barrier (BCB) disruption could be key elements in schizophrenia-spectrum disorders (SSDs) etiology and symptom modulation. We present the largest two-stage individual patient data (IPD) meta -analysis, investigating the association of BCB disruption and cerebrospinal fluid (CSF) alterations with symptom severity in first-episode psychosis (FEP) and recent onset psychotic disorder (ROP) individuals, with a focus on sex-related differences. Data was collected from PubMed and EMBASE databases. FEP, ROP and high-risk syndromes for psychosis IPD were included if routine basic CSF-diagnostics were reported. Risk of bias of the included studies was evaluated. Random-effects meta -analyses and mixed-effects linear regression models were employed to assess the impact of BCB alterations on symptom severity. Published (6 studies) and unpublished IPD from n = 531 individuals was included in the analyses. CSF was altered in 38.8 % of individuals. No significant differences in symptom severity were found between individuals with and without CSF alterations (SMD = -0.17, 95 %CI - 0.55 -0.22, p = 0.341). However, males with elevated CSF/ serum albumin ratios or any CSF alteration had significantly higher positive symptom scores than those without alterations (SMD = 0.34, 95 %CI 0.05 -0.64, p = 0.037 and SMD = 0.29, 95 %CI 0.17 -0.41p = 0.005, respectively). Mixed-effects and simple regression models showed no association (p > 0.1) between CSF parameters and symptomatic outcomes. No interaction between sex and CSF parameters was found (p > 0.1). BCB disruption appears highly prevalent in early psychosis and could be involved in positive symptoms severity in males, indicating potential difficult-to-treat states. This work highlights the need for considering BCB breakdown and sex-related differences in SSDs clinical trials and treatment strategies.

Background Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. Objective/Hypothesis In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. Methods Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. Results Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. Conclusions Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Previous studies have suggested that choroid plexus (ChP) enlargement occurs in individuals with schizophrenia-spectrum disorders (SSD) and is associated with peripheral inflammation. However, it is unclear whether such an enlargement delineates a biologically defined subgroup of SSD. Moreover, it remains elusive how ChP is linked to brain regions associated with peripheral inflammation in SSD. A cross-sectional cohort of 132 individuals with SSD and 107 age-matched healthy controls (HC) underwent cerebral magnetic resonance imaging (MRI) and clinical phenotyping to investigate the ChP and associated regions. A case-control comparison of ChP volumes was conducted, and structural variance was analyzed by employing the variability ratio (VR). K-means clustering analysis was used to identify subgroups with distinct patterns of the ventricular system, and the clusters were compared in terms of demographic, clinical, and immunological measures. The relationship between ChP volumes and brain regions, previously associated with peripheral inflammation, was investigated. We did not find a significant enlargement of the ChP in SSD compared to HC but detected an increased VR of ChP and lateral ventricle volumes. Based on these regions, we identified 3 clusters with differences in cognitive measures and possibly inflammatory markers. Larger ChP volume was associated with higher volumes of hippocampus, putamen, and thalamus in SSD but not in HC. This study suggests that ChP variability, but not mean volume, is increased in individuals with SSD, compared to HC. Larger ChP volumes in SSD were associated with higher volumes of regions previously associated with peripheral inflammation.

BACKGROUND:There is increasing evidence of immune dysregulation and neuroinflammation occurring in schizophrenia. The aim of this study is to combine studies on routine CSF parameters, as well as cytokines and inflammatory proteins, in individuals with schizophrenia spectrum disorders. METHODS:CSF parameters were summated and inverse variance meta-analyses using a random effects model were performed comparing mean difference or odds ratios. Between study heterogeneity was assessed using the I2 statistic. Quality assessment and sensitivity analyses were performed. RESULTS:There were 69 studies of 5710 participants, including 3180 individuals with schizophrenia spectrum disorders. Averaged CSF parameters were within normal limits, however, between 3.1 % and 23.5 % of individual cases with schizophrenia spectrum disorders had an abnormal CSF result: Protein (abnormal in 23.5 % cases), albumin (in 18.5 %), presence of oligoclonal bands (in 9.3 %), white blood cell count (in 3.6 %), and IgG levels (3.1 %). Meta-analysis of 55 studies with non-psychiatric controls demonstrated a significant increase in CSF total protein (MD: 3.50, CI: 0.12-6.87), albumin ratio (MD: 0.55, CI: 0.02-0.09), white cell count (MD: 0.25, CI: 0.05-0.46), IL-6 (SMD: 0.53, CI: 0.29 to 0.77) and IL-8 (SMD: 0.56, CI: 0.11 to 1.01). Sensitivity analysis did not alter findings. CONCLUSION:Abnormal CSF parameters, cytokines and inflammatory proteins were found in a significant proportion of individuals with schizophrenia spectrum disorders. This may indicate alterations to blood brain barrier function and permeability, CSF flow dynamics or neuroinflammation. Further research is needed to explore these potential mechanisms.

INTRODUCTION:Approximately 30% of individuals with schizophrenia experience treatment resistance (TR), with 70% exhibiting it from the onset. Most research fails to distinguish between acquired and innate resistance, with limited data on TR in first episode psychosis (FEP). However, FEP patients with TR experience progressively worse outcomes compared to those with initial response. To further understand these findings, clinical and demographic data of FEP patients with and without TR were compared in this naturalistic study. METHODS:Information was extracted on FEP patients who were antipsychotic-naive at the time of admission from a retrospective database on F2x diagnosed patients admitted to the LMU psychiatric clinic between 2008 and 2018. Clozapine was used at discharge as a marker of TR in the FEP cohort. A similarly antipsychotic-naïve FEP control group without clozapine at discharge, was generated by matching for gender and age. Thirty clinical and demographic variables were analyzed to identify differences. RESULTS:Two-hundred forty antipsychotic-naive FEPs were included: 33 with clozapine at discharge (TRC group), and 207 in the control group (non-TRC). Significant differences were observed in inpatient stay duration, chlorpromazine-equivalent dosage, number of antipsychotics, and anticholinergic medication at discharge. DISCUSSION:The findings indicate that longer inpatient stay, an increased number of antipsychotics, and possibly a more extended prodrome may serve as markers for non-clozapine TR in FEP. Further research is necessary to establish the robustness of these variables as early-stage TR markers.

BACKGROUND:The evidence for repetitive transcranial magnetic stimulation (rTMS) to treat negative symptoms in schizophrenia (SCZ) is increasing, although variable response rates remain a challenge. Subject´s sex critically influences rTMS´ treatment outcomes. Females with major depressive disorder are more likely to respond to rTMS, while SCZ data is scarce. METHODS:Using data from the 'rTMS for the Treatment of Negative Symptoms in Schizophrenia' (RESIS) trial we assessed the impact of sex on rTMS´ clinical response rate from screening up to 105 days after intervention among SCZ patients. The impact of resting motor threshold (RMT) on response rates was also assessed. RESULTS:157 patients received either active or sham rTMS treatment. No significant group differences were observed. Linear mixed model showed no effects on response rates (all p > 0.519). Apart from a significant sex*time interaction for the positive subscale of the positive and negative syndrome scale (PANSS) scores (p = 0.032), no other significant effects of sex on continuous PANSS scores were observed. RMT had no effect on response rate. CONCLUSION:In the largest rTMS trial on the treatment of SCZ negative symptoms we did not observe any significant effect of sex on treatment outcomes. Better assessments of sex-related differences could improve treatment individualisation.

Introduction: Concurrent TMS/fMRI has become a promising technique for investigating the acute effects of rTMS on the brain. However, image quality in concurrent TMS/fMRI may still have its limitations. In this study, we aimed to explore the data quality before concluding the findings from this state-of-the-art setup to ensure the imaging quality was sufficient for analysis. Methods: Nineteen healthy participants participated in this study. In the first session, we performed baseline MRI scans with a 64-channel head coil in a 3T Magnetom Prisma scanner and measured individual resting-motor thresholds (rMT). From the second to the fourth session, we performed scans with ultrathin 14-channel MR receive coils with a standard iTBS protocol and randomized three conditions for each participant: 80% or 40% rMT over the left DLPFC and 80% rMT over the left M1 region. In these sessions, structural scans (MP2RAGE sequence) and three functional scans were acquired, resting-state fMRI (rsfMRI) immediately before and after stimulation, and interleaved iTBS/fMRI. All rsfMRI data was preprocessed with bias field correction, despiking, segmentation, coregistration, normalization, and smoothing. Results: The mean TMS coil framewise displacement (FD) from the original target showed no significant difference between conditions. However, three subjects in the DLPFC 80% condition had coil displacement more than 3mm (Figure 1) related to TMS intolerance. MP2RAGE sequence provides satisfactory image quality, but the SNR and CNR are still inferior to the baseline T1w image (Figure 2). For fMRI imaging, we compared the SNR on both rsfMRI and interleaved iTBS/fMRI; all improved significantly after preprocessing (Figure 3). Discussions: This result demonstrates that the novel concurrent TMS/fMRI setup provides high-quality structural and functional scans. Additionally, the TMS coil had an acceptable FD range confirmed for further analysis. This study was supported by the Federal Ministry of Education and Research: ERA-NET NEURON,FKZ:01EW1903View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Research Category and Technology and Methods Translational Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: TMS, fMRI, Concurrent TMS/fMRI

INTRODUCTION:A neurobiological feature of Fetal Alcohol Spectrum Disorder (FASD) is a global decrease in neuronal connectivity, which leads to significant impairments in everyday functionality. Non-invasive repetitive transcranial magnetic stimulation (rTMS) could potentially positively influence neuronal plasticity but has not yet been studied in FASD. The present trial addresses this gap, making it the first-ever study of rTMS in FASD. MATERIALS AND METHODS:The prospective clinical trial was conducted at the LMU University Hospital Munich and enrolled eight FASD participants aged 6-16. Six sessions of 1 Hz-rTMS over the left dorsolateral prefrontal cortex were administered two times a week for three weeks consisting of 1500 pulses at 90 % of resting motor threshold in four trains of 375s. Outcome measures investigated feasibility and treatment response of rTMS on executive functions, attention/impulsivity, social-emotional regulation and quality of life (QoL) via standardized tests and the FASD parents' app. RESULTS:Adherence and retention rate were 100 %. Adverse events (AEs) were mild and self-limiting, resulting in a per-session risk of 53.3 %, with local paraesthesia accounting for 54.2 % of the AEs. There were individual relevant but no significant group-level improvements in the investigated functional cerebral domains or participants' QoL. The FASD parents' app showed no significant change in participants' daily functioning or caregivers' QoL. Caregivers' parental stress decreased significantly. CONCLUSION:FASD is a very complex disorder that is difficult to treat. In addition, comorbidities as atypical responses to pharmacotherapies are frequent. For this reason, non-invasive, innovative therapies for children with FASD have to be developed. For the first time, rTMS was shown to be safe, tolerable, and acceptable and thus well feasible in paediatric patients with FASD. Further clinical studies with larger samples are needed to identify effective stimulation protocols and to evaluate treatment response.

Background: Previous studies investigating disruptions in central nervous system (CNS) barriers in schizophrenia spectrum disorders (SSD) mainly focused on cerebrospinal fluid (CSF) markers, that cannot adequately assess blood-brain barrier (BBB) integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) represents a sensitive method for investigating subtle barrier breakdown in vivo. So far, only one pilot study has investigated BBB breakdown in SSD with DCE-MRI, in a relatively small cohort. We hypothesized higher leakage in SSD compared to HC, pathognomonic for a clinical sub-phenotype of SSD. Methods: Forty-five people with SSD and 42 age- and sex-matched healthy controls (HC) were included in the cross-sectional study and 41 SSD and 40 HC were included in the final analyses. Clinical characterization, cognitive assessments, blood and CSF analyses were conducted. Pharmacokinetic modelling (Patlak method) was implemented. The volume transfer constant Ktrans was calculated and Ktrans maps were compared between the groups to detect group differences in BBB leakage. Within the SSD cohort, the association between leakage and clinical characteristics was investigated. Results: Group comparisons of Ktrans maps showed higher leakage in SSD compared to HC on a whole brain level. The effect was more pronounced in first episode compared to multiple episode psychosis. No association was detected between leakage and measures of cognition, psychopathology, peripheral inflammation and albumin CSF/serum ratio. Discussion: This is the largest study to date investigating the BBB in SSD with DCE-MRI, allowing direct exploration of the BBB, compared to a healthy control group and the first study to implement this modality in a multimodal approach, with CSF, blood, clinical and cognitive assessments. The results provide the first in vivo evidence of higher BBB leakage on a whole brain level compared to HC.### Competing Interest StatementThe authors have declared that there are no conflicts of interest in relation to the subject of this study. General declaration of potential conflict of interests: EW has been invited to advisory boards from Recordati and Boehringer Ingelheim. PF received speaker fees by Boehringer Ingelheim, Janssen, Otsuka, Lundbeck, Recordati, and Richter and was member of advisory boards of these companies and Rovi. All other authors report no potential conflicts of interest. AH was member of advisory boards of Boehringer-Ingelheim, Lundbeck, Janssen, Otsuka, Rovi and Recordati and received paid speakership by these companies as well as by AbbVie and Advanz. He is editor of the German schizophrenia guideline.### Funding StatementThis research was not supported by any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. JM was supported by the research funding program "Foerderprogramm fuer Forschung und Lehre (FoeFoLe)", University Hospital, LMU Munich (project number 1167).### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee of the Ludwig-Maximilian University gave ethical approval for this workI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

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.

Abstract 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.

IntroductionTreatment 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. MethodsIn 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. ResultsHere, 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. DiscussionThe 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.

Introduction: Transparency and reproducibility are important quality attributes in science. However, privacy and data security limit the public use of raw datasets in platforms like Open Science Framework. One possibility is to anonymize MRI data and make the facial profile (nose, eyes, mouth) unrecognizable using tools such as the Python package pydeface. For full anonymization all facial data is removed from the MRI scan. This reliably prevents facial reconstruction, which occurs when head-mesh files are generated by SimNIBS. Therefore, we aimed to investigate whether defaced and full-faced scans result in different electric-fields (e-field) when using SimNIBS. Methods: We simulated e-field distributions (n = 17) with SimNIBS (Version 4.0b0). Transcranial Magnet Stimulation was applied over the left DLPFC at an intensity of 80% of the resting-motor threshold. For each subject, the simulation was conducted with T1- and T1-T2-weighted scans (scan type) with i) defaced and ii) full-faced scans, respectively. Results: The ANOVA revealed no significant differences between defaced and full-faced scans for all e-field percentiles (99.9%, 99.0%, 95.0%) and a main-effect of scan type for the 99.9% e-field percentile. Post-hoc analysis showed higher e-field values for T1-weighted than for T1-T2 weighted scans for the 99.9%-percentile. Discussion: In summary, for e-field simulations with SimNIBS4.0 defaced scans do not result in different outcomes than full-faced scans. SimNIBS4.0 automatically substitutes the missing facial data by template data, which might contribute to the low differences. But different scan types might lead to diverging results in the highest e-field percentile. By ensuring the same e-field output, future studies with SimNIBS should be performed with defaced images, allowing the community to share scans and head-mesh files with the interested public in the spirit of the Open Science concept. This work was supported by the Federal Ministry of Education and Research (BMBF): ERA-NET NEURON, FKZ: 01E[1] W1903. Research Category and Technology and Methods Basic Research: 10. Transcranial Magnetic Stimulation (TMS) Keywords: SimNIBS, defacing, TMS-simulation, electric-field

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.

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits.

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. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044

Background Schizophrenia spectrum disorders (SSDs) are presumed to be associated with retinal thinning. However, evidence is lacking as to whether these retinal alterations reflect a disease-specific process or are rather a consequence of comorbid diseases or concomitant microvascular impairment. Methods The study included 126 eyes of 65 patients with SSDs and 143 eyes of 72 healthy controls. We examined macula and optic disc measures by optical coherence tomography (OCT) and OCT angiography (OCT-A). Additive mixed models were used to assess the impact of SSDs on retinal thickness and perfusion and to explore the association of retinal and clinical disease-related parameters by controlling for several ocular and systemic covariates (age, sex, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking status, and OCT signal strength). Results OCT revealed significantly lower parafoveal macular, macular ganglion cell-inner plexiform layer (GCIPL), and macular retinal nerve fiber layer (RNFL) thickness and thinner mean and superior peripapillary RNFL in SSDs. In contrast, the applied OCT-A investigations, which included macular and peripapillary perfusion density, macular vessel density, and size of the foveal avascular zone, did not reveal any significant between-group differences. Finally, a longer duration of illness and higher chlorpromazine equivalent doses were associated with lower parafoveal macular and macular RNFL thickness. Conclusions This study strengthens the evidence for disease-related retinal thinning in SSDs.