Psychiatry’s reliance on language makes LLMs a natural tool for psychopathological assessment, yet structured, item-level assessments from psychiatric clinical interviews remain under-researched. In this proof-of-concept study, 10 LLMs assessed transcripts of three simulated psychiatric interviews across all 100 items of the Association for Methodology and Documentation in Psychiatry (AMDP) system, benchmarked against 108 early-career clinicians rating full audiovisual recordings, using an expert consensus panel as reference. GPT-5.1 and Gemini-3-Pro-Preview achieved the highest accuracy (0.72; 64th percentile of the clinician distribution) using majority voting across three runs with AMDP definitions as context. GPT-5.1, selected for a marginal advantage, showed per-scenario accuracies of 0.81 (depression), 0.76 (mania), and 0.60 (schizophrenia) versus clinician means of 0.79, 0.68, and 0.58. Clinicians and LLMs showed distinct error profiles: clinicians tended to over-infer symptom presence, whereas LLMs more conservatively flagged items as “not assessable” — most pronounced for observation-dependent items but present even for text-assessable items (19.4% vs. 11.4%, p < 0.001). In post hoc simulated disagreement resolutions (2091 clinician pairs; 35.5% disagreements), LLM and board-certified supervision were associated with more accurate resolutions than unsupervised random clinician selection (p < 0.0002). These proof-of-concept findings require validation in real patient interviews, larger samples, and prospective studies integrating multimodal input.

Introduction:Previous studies suggest a problem in the care of long-term patients in psychiatry, i.e., patients with long hospitalizations and no indication for acute inpatient treatment. Long stays are often associated with treatment resistance, for which evidence-based guideline recommendations exist for patients with schizophrenia. The aim of this study is to assess and characterize long-term patients in German psychiatric clinics and analyze the implementation of guideline recommendations for treatment-resistant schizophrenia. Methods:An anonymous online questionnaire was distributed to the management of 218 acute psychiatric clinics in Germany. The survey covered structural characteristics of the clinic, the number and diagnoses of long-term patients, and the implementation of guideline recommendations for patients with treatment-resistant schizophrenia. Results:At the time of the survey, two-thirds of the responding clinics were treating long-term patients. Over 60% (n=45) of these patients had a diagnosis from the schizophrenia spectrum, with an average length of stay of 267 days. A total of 82.2% of patients with schizophrenia received antipsychotic therapy, 53% received clozapine, and 15.6% received electroconvulsive therapy. The most common reason for not receiving clozapine and electroconvulsive therapy was lack of consent. Discussion:The survey confirms the unresolved problem of long-term patients in acute psychiatric clinics. In addition to demands for improved care structures for people with severe and chronic mental illnesses, the quality of acute psychiatric treatment (guideline adherence) must also be questioned. From an ethical viewpoint, short-term nonvoluntary measures aimed at restoring capacity to consent need to be weighed up against long-term or even permanent detention.

BACKGROUND:Kappa free light chains (KFLC) are a surrogate parameter for intrathecal immunoglobulin G (IgG), immunoglobulin M (IgM) and immunoglobulin A (IgA) synthesis confirming neuroinflammation in the central nervous system (CNS). It is unclear whether KFLC can differentiate primary psychiatric disorders from neural autoantibody-associated psychiatric syndromes. METHODS:We enrolled 76 patients with psychiatric diagnoses ICD-10 (International Classification of Diseases, 10th revision) (F00-09, F10-19, F20-29, F30-39, F40-49) and cerebrospinal fluid (CSF) as well as blood samples from our biobank. Commercial assays were used to determine neural autoantibodies. KFLC in serum and CSF samples were assessed by nephelometry (Siemens Atellica NEPH 630 analyzer). We calculated the relative intrathecal fraction (IF) of KFLC and the KFLC index using KFLC quotient and albumin quotient. Criteria for autoimmune encephalitis and autoimmune-mediated psychiatric syndromes were evaluated in patients to determine an autoimmune basis for the psychiatric symptoms. RESULTS:Neither the number of patients with elevated KFLC, a KFLC index nor the KFLC IF percentage served as an instrument for differentiating between autoantibody-positive (n = 18) and autoantibody-negative (n = 58) psychiatric patients. Patients with elevated KFLC levels in CSF had a higher proportion of lymphocytes than patients with non-elevated KFLC as a non-significant trend. We observed a non-significant trend towards higher CSF/serum IgM, but no trend for CSF/serum IgA or CSF/serum IgG ratio in patients with elevated KFLC levels than in those with non-elevated KFLC. No probable autoantibody-positive or seronegative autoimmune encephalitis was detected in patients. However, we observed an autoantibody-associated psychiatric syndrome in 6 out of 10 patients with elevated KFLC-IF, and the detection of elevated KFLC improved the diagnosis of probable autoimmune disease in 4 out of 10 patients (40 %). CONCLUSIONS:Elevated KFLC levels may indicate psychiatric patients presenting any intrathecal immunoglobulin synthesis and thus help to evaluate an autoimmune basis in psychiatric syndromes. Furthermore, it should be added as a novel criterion for intrathecal immunoglobulin synthesis in autoimmune-related psychiatric syndromes. Further large-scale research is needed to elucidate the role of KFLC in autoimmune-mediated psychiatric disorders and to verify the observed trends in CSF parameters in patients with elevated KFLC.

BACKGROUND:A better mechanistic understanding of schizophrenia spectrum disorders is crucial to developing efficient treatment approaches. Therefore, this study investigated longitudinal interrelations between clinical outcomes, brain structure, and somatic health in post-acute individuals from the schizophrenia spectrum. METHODS:A sample of 63 post-acute patients from two independent physical exercise studies was included in the final analyses. Demographic, clinical, cognitive, and somatic data were acquired at baseline and follow-up, as were structural magnetic resonance imaging scans. Multivariate cross-lagged panel modeling including mediators was used to study the mutual interrelations over time between the clinical, neural, and somatic levels. RESULTS:A higher baseline global gray matter volume and larger regional gray matter volumes of the hippocampal formation, precuneus, and posterior cingulate predicted improved clinical outcomes, such as daily-life functioning, negative symptoms, and cognition. Increases in white matter volume from baseline to follow-up resulted in significantly reduced positive symptoms and higher daily-life functioning. CONCLUSIONS:Our findings suggest that stimulating neuroplasticity, especially in the hippocampal formation, precuneus, and posterior cingulate gyrus, may represent a promising treatment target in post-acute schizophrenia spectrum disorders. Physical exercise therapies and other lifestyle interventions, and brain stimulation approaches reflect potential treatment candidates. Given the exploratory character of the statistical analysis performed, these findings need to be replicated in independent longitudinal imaging cohorts of patients with schizophrenia spectrum disorders.

Research into the causes of mood disorders has been going on for decades. However, most of the hypotheses put forward have been insufficiently substantiated by living biomarkers. Much research is therefore being conducted into biomarkers that help us better assess the diagnosis and course of mood disorders. Neural autoantibodies are one such biomarker potentially appearing in a subgroup of mood disorders. The aim of this narrative review is to describe the spectrum of autoantibodies in mood disorders while substantiating their prevalence, about which there is very inconsistent evidence. In addition, we discuss autoantibodies in the context of systemic autoimmune diseases associated with depressive symptoms. The pathogenicity of individual autoantibodies has occasionally been demonstrated in animal models, and there is evidence that the severity of depressive symptoms correlates with certain autoantibodies. Possible models of autoimmunity are also explained, such as involvement of the B-cell system, the complement system, and systemic inflammation in autoimmune processes. Nevertheless, note that the mere presence of autoantibodies does not justify the assumption of an autoimmune genesis, as more evidence is needed. The aim of this review is to describe the concepts behind targeting autoantibodies in mood disorders.

A history of viral infection has been associated with a higher risk for psychiatric disorders. One potential underlying mechanism is that antiviral immunological responses could trigger cross-reactivity between viral and neural antigens, which would raise the co-occurrence of antiviral antibodies and anti-neural autoantibodies. We studied 619 patients’ psychiatric diagnoses from the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Germany. Anti-neural autoantibodies and antiviral antibody specific indices were measured in serum and/or cerebrospinal fluid (CSF) from all patients. Among these 619 patients, 115 tested positive for serum and/or CSF neural autoantibodies (18.6

Schizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Physical exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to physical exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n = 134) and 3- or 6-month post-exercise (n = 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline BMI demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD. Keywords: schizophrenia spectrum disorders, brain age gap, physical exercise, neuroplasticity, brain recovery, treatment response, polygenic risk ### Competing Interest Statement PF is a co-editor of the German (DGPPN) schizophrenia treatment guidelines and a co-author of the WFSBP schizophrenia treatment guidelines; he is on the advisory boards and receives speaker fees from Boehringer-Ingelheim, Janssen, Lundbeck, Otsuka, Servier, and Richter. JHC is a scientific advisor to and shareholder in Brain Key and Claritas HealthTech PTE. DY, AS, DK, BM, SP, IM, and LR declare no conflicts of interest or financial disclosures relevant to this research. There was no role of the sponsors in relation to the study design, collection, analysis and interpretation of data, writing of the report, and the decision to submit the article for publication. ### Clinical Trial NCT01776112, [NCT03466112][1] ### Clinical Protocols ### Funding Statement The work was supported by the German Federal Ministry of Education and Research (BMBF) through the research network on psychiatric diseases ESPRIT (Enhancing Schizophrenia Prevention and Recovery through Innovative Treatments; coordinator: Andreas Meyer-Lindenberg; grant number, 01EE1407E) awarded to PF and AS. Furthermore, the study was supported by the Else Kroener-Fresenius Foundation with the Research College Translational Psychiatry for PF, AS, and IM (Residency/PhD track of the International Max Planck Research School for Translational Psychiatry [IMPRS-TP]), and Max Planck School of Cognition, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, for DY. The study was endorsed by the Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung [BMBF]) within the initial phase of the German Center for Mental Health (DZPG) (grant: 01EE2303A, 01EE2303F to PF, AS). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Ludwig Maximilian University of Munich gave ethical approval for this work. I 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Explicit permission for data sharing was not included in the informed consent obtained during the data collection phase. As a result, and due to the sensitive nature of the clinical data, we are unable to share the data publicly. However, the data can be made available to individual researchers upon request. Researchers interested in accessing the data may contact us directly to discuss potential arrangements. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03466112&atom=%2Fmedrxiv%2Fearly%2F2025%2F01%2F08%2F2025.01.08.24319554.atom

Paranoid schizophrenia is a severe mental illness with both positive and negative symptoms. Currently, the role of peripheral and central inflammation is increasingly suspected as possible factor in the pathogenesis of schizophrenia. This retrospective, monocentric pilot study investigated 35 patients (15/35 female) diagnosed with paranoid schizophrenia after exclusion of possible underlying neuroinflammatory disorders to assess for inflammatory changes of the cerebrospinal fluid (CSF) and associated signs of neurodegeneration. Kappa free light chains (KFLC), a panel of 21 cyto- and chemokines, and neurofilament light chains (NFL) as surrogate parameters for neuro-inflammation and -degeneration were determined in patients with paranoid schizophrenia as well as age- and sex-matched inflammatory (n = 35) and non-inflammatory controls (n = 40). Patients with paranoid schizophrenia exhibited significantly higher intrathecal synthesized fractions of KFLC than non-inflammatory controls. KFLC-positive patients with paranoid schizophrenia had significantly higher NFL concentrations in CSF than KFLC-negative patients according to Reiber´s diagram. NFL concentrations in CSF of patients with paranoid schizophrenia were associated with illness duration, frequency of psychotic episodes, and amount of antipsychotic treatment attempts. This pilot study highlights inflammatory changes in the CSF among a specific subgroup of patients with paranoid schizophrenia, positively correlating with elevated NFL levels in CSF.

Schizophrenia spectrum disorders (SSD) are associated with accelerated brain aging, reflected in an increased brain age gap. This gap serves as a biomarker, indicating poorer brain health, cognitive deficits, and greater severity in specific symptom domains. Exercise holds promise as an adjunct therapy to mitigate these deficits by potentially promoting brain recovery. However, the extent of overall improvements in brain health following exercise, along with their predictors and relationships to symptom clusters, are yet to be determined. This study examined the brain age gap metric as a quantitative indicator of brain recovery in response to exercise. To achieve this, we aggregated data from two randomized controlled trials, analyzing baseline (n = 134) and 3- or 6-month post-exercise (n = 46) data from individuals with SSD. Our findings revealed that patients with a higher baseline body mass index (BMI) demonstrated greater brain recovery, as evidenced by a reduced brain age gap post-exercise. Furthermore, changes in the brain age gap were associated with improvements in negative symptoms and cognition, suggesting that reductions in brain-predicted age may reflect symptom relief, particularly in domains beyond positive symptoms. These results underscore the importance of BMI in brain health, support using the brain age gap as a surrogate marker for tracking clinically relevant brain recovery, and highlight the need for stratified interventions and combined lifestyle modifications to enhance outcomes in SSD.

Underlying biological mechanisms leading to the dramatically increased cardiac mortality in patients with schizophrenia (SCZ) are largely unknown. Cardiac autonomic dysfunction (CADF), which has been extensively described in patients with SCZ, represents an important physiological link to cardiovascular disease (CVD). This study investigated the prevalence of CADF in patients with SCZ using HRV across multiple domains (time and frequency, nonlinear dynamics, complexity measures, symbolic dynamics, and segmented Poincaré plot analysis). HRV-based clustering classified 119 SCZ patients as having or not having CADF based on deviations from 119 age- and sex-matched healthy controls. Our findings showed that approximately half of the patients had normal cardiac autonomic function, while the other half had significant abnormalities. The severity of CADF correlated with age, body mass indes (BMI), disease duration, and symptom severity. About half of SCZ patients have significant CADF, which increases their risk for cardiac events. These findings highlight the potential of HRV-based biomarkers in improving CVD risk prediction and stratification in SCZ. Future research should explore integrating HRV analysis with other biomarkers to enhance early detection and intervention strategies.

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.

Affiliations: In the published publication [...].

Cardiac autonomic dysfunction (CADF), mainly characterized by increased heart rate, decreased heart rate variability, and loss of vagal modulation, has been extensively described in patients with schizophrenia (SCZ) and their healthy first-degree relatives. As such, it represents an apparent physiological link that contributes to the increased cardiovascular mortality in these patients. Common genetic variation is a putative underlying mechanism, along with lifestyle factors and antipsychotic medications. However, the extent to which CADF is associated with genetic factors for SCZ is unknown. A sample of 83 drug-naive SCZ patients and 96 healthy controls, all of European origin, underwent a 30-minute autonomic assessment under resting conditions. We incorporated parameters from several domains into our model, including time and frequency domains (mean heart rate, low/high frequency ratio) and compression entropy, each of which provides different insights into the dynamics of cardiac autonomic function. These parameters were used as outcome variables in linear regression models with polygenic risk scores (PRS) for SCZ as predictors and age, sex, BMI, smoking status, principal components of ancestry and diagnosis as covariates. Of the three CADF parameters, SCZ PRS was significantly associated with mean heart rate in the combined case/control sample. However, this association was was no longer significant after including diagnosis as a covariate (p = 0.29). In contrast, diagnostic status is statistically significant for all three CADF parameters, accounting for a significantly greater proportion of the variance in mean heart rate compared to SCZ PRS (approximately 16

Background: The hippocampal formation represents a key region in the pathophysiology of schizophrenia. Aerobic exercise poses a promising add-on treatment to potentially counteract structural impairments of the hippocampal formation and associated symptomatic burden. However, current evidence regarding exercise effects on the hippocampal formation in schizophrenia is largely heterogeneous. Therefore, we conducted a systematic review and meta-analysis to assess the impact of aerobic exercise on total hippocampal formation volume. Additionally, we used data from a recent multicenter randomized-controlled trial to examine the effects of aerobic exercise on hippocampal formation subfield volumes and their respective clinical implications.Methods: The meta-analysis comprised six studies that investigated the influence of aerobic exercise on total hippocampal formation volume compared to a control condition with a total of 186 people with schizophrenia (100 male, 86 female), while original data from 29 patients (20 male, 9 female) was considered to explore effects of six months of aerobic exercise on hippocampal formation subfield volumes.Results: Our meta-analysis did not demonstrate a significant effect of aerobic exercise on total hippocampal formation volume in people with schizophrenia, but our original data suggested significant volume increases in certain hippocampal subfields such as the cornu ammonis and dentate gyrus.Conclusions: Driven by the necessity of better understanding the pathophysiology of schizophrenia, the present work underlines the importance to focus on hippocampal formation subfields and to characterize subgroups of patients that show neuroplastic responses to aerobic exercise accompanied by corresponding clinical improvements.

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.Clinical trials registration The study of this manuscript which the manuscript is based was registered in the International Clinical Trials Database, ClinicalTrials.gov (NCT number: NCT03466112, https://clinicaltrials.gov/ct2/show/NCT03466112?term=NCT03466112&draw=2&rank=1 ) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804.