Dong-Dong Shi

Aims: Compound Ciwujia Granules (CWJ) have shown antidepressant‐like effects, but the neural and molecular mechanisms underlying these effects remain unclear. This study aimed to investigate the mechanisms by which CWJ ameliorates anxiety‐ and depression‐like behaviors. Methods: A 6‐week chronic unpredictable mild stress (CUMS) model was established in rats, and behavioral tests were performed to assess the antidepressant‐like effects of CWJ. Resting‐state functional magnetic resonance imaging (rs‐fMRI), in vivo fiber photometry, and chemogenetic manipulation were used to identify the brain region and neuronal population involved in the effects of CWJ. Transcriptomic analysis combined with network pharmacology was used to predict candidate molecular pathways, which were further validated by quantitative real‐time polymerase chain reaction, immunofluorescence, western blotting, and pharmacological interventions. Results: CWJ increased the open‐arm ratio in the EPM, reduced FST immobility, and lowered serum corticosterone (CORT) levels in CUMS rats. Convergent rs‐fMRI, c‐Fos immunostaining, and fiber photometry identified that the dorsomedial prefrontal cortex (dmPFC) was a key brain region involved in the antidepressant‐like effects of CWJ. CWJ increased glutamatergic neuronal activity and reduced neuroinflammatory responses associated with TNF‐related inflammatory signaling in the dmPFC. Moreover, pharmacological activation of TNF‐related inflammatory signaling partially attenuated the behavioral benefits of CWJ, supporting the involvement of TNF‐related inflammatory signaling in mediating its antidepressant effects. Conclusions: These findings suggest that CWJ attenuated CUMS‐induced anxiety‐ and depression‐like behaviors by restoring dmPFC glutamatergic neuronal activity and suppressing TNF‐related neuroinflammation in the dmPFC.

Emerging evidence indicates that gut microbiota influences host physiology and behavior through the microbiota‐gut‐brain axis, potentially contributing to the pathogenesis of obsessive‐compulsive disorder (OCD). Our preliminary research demonstrated that mice colonized with fecal microbiota from OCD patients developed compulsive‐like behaviors, associated with a significant increase in the microbial metabolite succinate. However, the mechanisms linking succinate to compulsive‐like behavior remain to be fully elucidated. Here, we demonstrate that succinate is associated with significant compulsive‐like behaviors. Succinate is associated with disruptions of glutamatergic neurons within the dorsal medial prefrontal cortex (dmPFC), and we characterize dual pathways linked to the behavioral abnormality: both by dmPFC microglial engagement via the succinate cognate receptor SUCNR1, and by gut‐to brain signaling conveyed through vagal afferents and the 5‐HT ₄ receptor. Pharmacological modulation of the succinate metabolism pathway through succinate dehydrogenase inhibition ameliorates compulsive‐like behavior in Hoxb8 ^−/− OCD‐model mice. Circulating succinate levels significantly distinguish OCD patients from healthy controls with an AUC of 0.73, and correlate with prefrontal cortex activity on functional imaging. Collectively, our study delineates a gut‐brain axis implicating succinate in central nervous system dysregulation associated compulsive‐like behavior, elucidates novel immunometabolism and neural circuit mechanisms underlying OCD pathogenesis, and identifies druggable targets for potential precise interventions.

Objective: Estimating clinically important differences (CIDs) for patient‐reported outcome measures (PROMs) is essential for translating statistical findings into clinically meaningful treatment effects. We developed estimating clinically important differences (ESTICID), a cross‐platform toolkit implemented in both R Shiny and statistical analysis system, to estimate and visualise CIDs in longitudinal studies. Methods: ESTICID applies an anchor‐based approach using linear mixed‐effects models with random intercepts. The framework accommodates repeated measures, supports both continuous and categorical anchors and handles incomplete follow‐up data under a missing‐at‐random assumption. A multicenter randomised controlled trial dataset was used for illustration. Examples: Using the illustrative dataset, we show that ESTICID generates clinically interpretable CID estimates across different levels of improvement and provides graphical outputs that facilitate interpretation. In simulation analyses, the estimates remained stable under increasing levels of missing follow‐up data. The R Shiny implementation further enables interactive, browser‐based use without programming. Conclusions: ESTICID provides a practical and accessible framework for anchor‐based CID estimation in longitudinal PROM research. By integrating methodological rigour with cross‐platform implementation, it may improve the interpretation of treatment effects, responder definitions, sample size estimation and evidence‐to‐decision processes in psychiatry and related clinical fields.

This paper aims to present a Statistical Analysis Software (SAS) macro %BBIplus, offering estimation and visualisation methods for the Bang’s Blinding Index (BBI) for randomised controlled trials (RCTs) with various designs. We developed the SAS macro programme %BBIplus to facilitate the implementation of BBI. This user‐friendly programme allows for easy and rapid estimation and visualisation of BBI across different scenarios, including pairwise comparison RCTs with two arms, double‐dummy design RCTs with three arms and factorial design RCTs with four arms. The programme requires no pre‐existing data set, and users only need to input the number of individuals of correct, uncertain or wrong guesses in each intervention or control group. We illustrate the functionality of %BBIplus using blinding assessment data from three previously published RCTs: BBR (adjunctive berberine reduces antipsychotic‐associated weight gain and metabolic syndrome in patients with schizophrenia: a randomised controlled trial), SELECT‐TDCS (the sertraline versus electrical current therapy for treating depression clinical study: results from a factorial, randomised controlled trial) and ELECT‐TDCS (trial of electrical direct‐current therapy versus escitalopram for depression) studies. The programme estimates the BBI for each arm, providing point estimates, 95% CI and associated p values. Additionally, %BBIplus can visualise the estimations through forest plots and make the judgement for the success of blinding easily and rapidly. This tool caters to the needs of clinical trial investigators, offering a comprehensive solution for estimating and visualising the blinding index under various RCT designs.

Research suggests that individuals who experience prolonged exposure to stress may be at higher risk for developing psychological stress disorders. Currently, psychological stress is primarily evaluated by professional physicians using rating scales, which may be prone to subjective biases and limitations of the scales. Therefore, it is imperative to explore more objective, accurate, and efficient biomarkers for evaluating the level of psychological stress in an individual. In this study, we utilized 4D data-independent acquisition (4D-DIA) proteomics for quantitative protein analysis, and then employed support vector machine (SVM) combined with SHAP interpretation algorithm to identify potential biomarkers for psychological stress levels. Biomarkers validation was subsequently achieved through machine learning classification and a substantial amount of a priori knowledge derived from the knowledge graph. We performed cross-validation of the biomarkers using two batches of data, and the results showed that the combination of Glyceraldehyde-3-phosphate dehydrogenase and Fibronectin yielded an average area under the curve (AUC) of 92%, an average accuracy of 86%, an average F1 score of 79%, and an average sensitivity of 83%. Therefore, this combination may represent a potential approach for detecting stress levels to prevent psychological stress disorders.

Obsessive-compulsive disorder (OCD) is a chronic, severe psychiatric disorder that has been ranked by the World Health Organization as one of the leading causes of illness-related disability, and first-line interventions are limited in efficacy and have side-effect issues. However, the exact pathophysiology underlying this complex, heterogeneous disorder remains unknown. This scenario is now rapidly changing due to the advancement of powerful technologies that can be used to verify the function of the specific gene and dissect the neural circuits underlying the neurobiology of OCD in rodents. Genetic and circuit-specific manipulation in rodents has provided important insights into the neurobiology of OCD by identifying the molecular, cellular, and circuit events that induce OCD-like behaviors. This review will highlight recent progress specifically toward classic genetic animal models and advanced neural circuit findings, which provide theoretical evidence for targeted intervention on specific molecular, cellular, and neural circuit events.

Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive-compulsive disorder (OCD). Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice and showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16 S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD-colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota–brain–immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice. We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.

Oxytocin (OXT), produced and secreted in the paraventricular nucleus and supraoptic nucleus of magnocellular and parvocellular neurons. The diverse presence and activity of oxytocin suggests a potential for this neuropeptide in the pathogenesis and treatment of stress-related neuropsychiatric disorders (anxiety, depression and post-traumatic stress disorder (PTSD)). For a more comprehensive understanding of the mechanism of OXT's anti-stress action, the signaling cascade of OXT binding to targeting stress were summarized. Then the advance of OXT treatment in depression, anxiety, PTSD and the major projection region of OXT neuron were discussed. Further, the efficacy of endogenous and exogenous OXT in stress responses were highlighted in this review. To augment the level of OXT in stress-related neuropsychiatric disorders, current biological strategies were summarized to shed a light on the treatment of stress-induced psychiatric disorders. We also conclude some of the major puzzles in the therapeutic uses of OXT in stress-related neuropsychiatric disorders. Although some questions remain to be resolved, OXT has an enormous potential therapeutic use as a hormone that regulates stress responses.