BACKGROUND:Adolescent depression shows clear sex differences, with females having higher prevalence and more severe symptoms than males. The biological basis of these differences, particularly involving inflammation and the gut-brain axis, remains poorly understood. This study investigated sex-specific clinical and biological features and their value in predicting non-suicidal self-injury (NSSI) in adolescents with major depressive disorder (MDD). METHODS:Ninety-two adolescents with MDD were assessed using the Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale. Serum levels of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-4, IL-8), gut barrier markers (iFABP, LBP), and blood-brain barrier (BBB) markers (S100β, claudin-5) were measured. Associations were examined using Spearman correlation, and logistic regression was applied to identify predictors of NSSI in females. RESULTS:Female patients had more severe depressive and anxiety symptoms and higher TNF-α levels than males. Gut and BBB markers were positively correlated, indicating gut-brain axis involvement. Logistic regression showed that younger age (OR < 1) and higher S100β levels (OR > 1) significantly predicted NSSI in females. The gut-brain biomarker model showed the best predictive performance (AUC = 0.844). CONCLUSION:Adolescents with MDD exhibit sex-specific clinical and biological profiles. Younger age and increased BBB permeability, reflected by elevated S100β, are key predictors of NSSI in females. Gut-brain axis biomarkers may aid early risk identification and targeted intervention in adolescent depression.

Emerging evidence links immune activation to antidepressant response in adolescents with major depressive disorder (MDD). We examined how depressive symptoms, quality of life (QOL), and blood markers of inflammation, blood–brain barrier (BBB) integrity, and gut permeability change following antidepressant treatment in this population. Twenty-six adolescents with MDD were evaluated at baseline (pre-treatment), 12 weeks, and 24 weeks after starting therapy. Depression and anxiety were measured by the Hamilton Depression Rating Scale (HAMD) and Hamilton Anxiety Rating Scale (HAMA). QOL was assessed with the QOL Scale for Children and Adolescents (QLSCA) and an adolescent social support instrument. Serum levels of IL-1β, TNF-α, IL-6, IL-4, S100β, claudin-5, LBP, I-FABP, and brain-derived neurotrophic factor (BDNF) were quantified. At baseline, pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and IL-4 strongly correlated with BBB (S100β, claudin-5) and gut-permeability (I-FABP) markers. IL-4 levels rose significantly and were associated with reduced anxiety (HAMA: r = −0.48, p < 0.05) and better QOL (QLSCA: r = 0.57, p < 0.01). BBB integrity and gut-permeability markers remained stable. In responders only, BDNF increased at 12 weeks (p < 0.05) and IL-8 rose at 24 weeks (p < 0.05), suggesting their involvement in treatment efficacy. Antidepressant therapy in adolescents with MDD is accompanied by dynamic elevations in IL-4, IL-8, and BDNF that parallel clinical improvement and enhanced QOL. These biomarkers warrant further study to develop more targeted interventions for adolescent depression. Not applicable.

The pathogenesis of neuropsychiatric disorders, including autism spectrum disorder and schizophrenia, originates from complex interactions between genetic susceptibility and early environmental exposure. Infectious challenges during pregnancy are well-known environmental risk factors for neurodevelopmental disorders. Our previous research reported the interplay between maternal immune activation (MIA) and nucleotide-binding oligomerization domain-containing protein 2 (Nod2) signaling deficiency as potential genetic and environmental risk factors for schizophrenia pathogenesis. However, the mechanisms underlying this double-hit interaction—specifically regarding maternal-fetal interface homeostasis—remain unclear. In this study, we used the novel double-hit murine model that combines Nod2 knockout (Nod2−/−) with polyinosinic:polycytidylic acid-induced MIA to systematically assess maternal metabolic profiles, placental developmental dynamics, and offspring behavioral phenotypes. We demonstrated that double-hit exposure has a significant effect on maternal metabolism and offspring development, characterized by sex-specific functional alterations in the placenta and increased susceptibility to neurodevelopmental disorders in male offspring. These results confirmed that the maternal environment modulates offspring neurodevelopment through placental mediation, highlighting the potential of modulating maternal immune-metabolic homeostasis as a preventive strategy against neurodevelopmental disorders.

INTRODUCTION:Schizophrenia is a severe mental disorder with a complex etiopathogenesis involving both genetic and environmental risk factors. Evidence suggests that immune dysregulation plays a key role in its development, with maternal immune activation (MIA) during pregnancy identified as a significant environmental contributor. However, not all maternal infections result in schizophrenia-like outcomes, indicating that genetic susceptibility may render some individuals more vulnerable to MIA. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular receptor, plays a crucial role in maintaining the balance between intestinal microbiota and immune responses, but its precise role in gut-brain interactions during neurodevelopment remain unclear. METHODS:To investigate the interaction between MIA and Nod2 deficiency, we evaluated behavioral and physiological phenotypes in Nod2-/- mice exposed to poly(I:C)-induced MIA. In addition to immune responses, we analyzed maternal gut microbiota and the transmission of microbiota between mothers and offspring. Given the role of the gut-brain axis in schizophrenia, we conducted intestinal immunofluorescence staining, organoid cultures, and RNA sequencing of fetal brains to assess gut injury and neuroimmune changes in the brain. Male and female offspring were analyzed separately. RESULTS:Dual exposure led to schizophrenia-like behaviors in a sex-specific manner, as well as brain development disruptions, compromised gut integrity, reduced intestinal organoid-forming capacity, and altered gut microbiota composition. Importantly, maternal gut microbiota disturbances, coupled with microbial transmission to offspring, appear to increase schizophrenia risk with potential long-term behavioral consequences. CONCLUSION:This study underscores the intricate interplay of genetic, environmental, and microbiome factors, offering a valuable model for investigating the complex pathophysiology of neurodevelopmental disorders.

Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain.

Background Childhood neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and Tourette syndrome (TS), comprise a major cause of health-related disabilities in children. However, biomarkers towards pathogenesis or novel drug targets are still limited. Our study aims to provide a comprehensive investigation of the causal effects of the plasma proteome on ASD, ADHD, and TS using the two-sample Mendelian Randomization (MR) approach. Methods Genetic associations with 2994 plasma proteins were selected as exposures and genome-wide association data of ASD, ADHD, TS were utilized as outcomes. MR analyses were carried out using the inverse-variance weighted method, and the MR-Egger and weighted median methods were used for sensitivity analysis. Findings Using single-nucleotide polymorphisms as instruments, the study suggested increased levels of MAPKAPK3 (OR: 1.09; 95% CI: 1.05-1.13; P = 1.43 x 10-6) and MRPL33 (OR: 1.07; 95% CI: 1.04-1.11; P = 5.37 x 10-6) were causally associated with a higher risk of ASD, and increased MANBA level was associated with a lower risk of ADHD (OR: 0.91; 95% CI: 0.88-0.95; P = 8.97 x 10-6). The causal associations were robust in sensitivity analysis, leave-one-out analysis and Multivariable MR, and no pleiotropy was observed. No significant risk protein was identified for TS. Interpretation The study findings support the idea that the MAPK/ERK signaling pathway and mitochondrial dysfunction are involved in the pathogenesis of ASD, while a deficiency in beta-mannosidase might play a role in the development of ADHD Copyright (c) 2022 The Author(s). Published by Elsevier B.V.

Schizophrenia (SCZ) is associated with several immune dysfunctions, including elevated levels of pro-inflammatory cytokines. Microorganisms and their metabolites have been found to regulate the immune system, and that intestinal microbiota is significantly disturbed in schizophrenic patients. To systematically investigate aberrant gut-metabolome-immune network in schizophrenia, we performed an integrative analysis of intestinal microbiota, serum metabolome, and serum inflammatory cytokines in 63 SCZ patients and 57 healthy controls using a multi-omics strategy. Eighteen differentially abundant metabolite clusters were altered in patients displayed higher cytokine levels, with a significant increase in pro-inflammatory metabolites and a significant decrease in anti-inflammatory metabolites (such as oleic acid and linolenic acid). The bacterial co-abundance groups in the gut displayed more numerous and stronger correlations with circulating metabolites than with cytokines. By integrating these data, we identified that certain bacteria might affect inflammatory cytokines by modulating host metabolites, such as amino acids and fatty acids. A random forest model was constructed based on omics data, and seven serum metabolites significantly associated with cytokines and α-diversity of intestinal microbiota were able to accurately distinguish the cases from the controls with an area under the receiver operating characteristic curve of 0.99. Our results indicated aberrant gut-metabolome-immune network in SCZ and gut microbiota may influence immune responses by regulating host metabolic processes. These findings suggest a mechanism by which microbial-derived metabolites regulated inflammatory cytokines and insights into the diagnosis and treatment of mental disorders from the microbial-immune system in the future.

Amino acid abnormalities have been suggested to be a key pathophysiological mechanism in schizophrenia (SZ). Recently, gut microbes were found to be critically involved in mental and metabolic diseases. However, the relationship between serum amino acid levels and gut microbes in SZ is rarely studied. Here, we analyzed serum amino acid levels in 76 untreated SZ patients and 79 healthy controls (HC). Serum levels of 10 amino acids were significantly altered in patients with SZ. We further classified the cut-off values for serum arginine, leucine, glutamine, and methionine levels to distinguish SZ patients from controls. These classifiers were shown to be effective in another validation cohort (49 SZ and 48 HC). The correlation between serum amino acids and clinical symptoms and cognitive functions was also analyzed. Arginine, leucine, glutamine, and methionine levels were significantly correlated with clinical symptoms and cognitive impairments in SZ patients. By metagenome shotgun sequencing of fecal samples, we found that patients with SZ with a low level of serum amino acids have higher richness and evenness of the gut microbiota. At the genus level, the abundances of Mitsuokella and Oscillibacter are significantly abnormal. At the mOTU level, 15 mOTUs in the low-level SZ group were significantly different from the HC group. In addition, Mitsuokella multacida was correlated with glutamine and methionine, respectively. Our research revealed that alterations in serum amino acid levels are critically related to changes in gut microbiota composition in SZ patients. These findings may shed light on new strategies for the diagnosis and treatment of SZ.

Introduction: Bilateral hemifacial spasm (HFS) is rare. Clinico-radiologic correlates utilizing advanced imaging techniques have not been systematically examined in bilateral HFS. The prevalence of bilateral HFS in an Asian population has not been clarified. Objectives: We examined the prevalence and clinico-radiologic correlates of bilateral HFS in a clinic-based cohort and compared the clinical characteristics of unilateral HFS patients with and without contralateral neurovascular contact (NVC) in HFS. Methods: Patients clinically diagnosed with HFS were examined for bilateral symptoms. Imaging analysis involved the utilization of reformatted, multi-planar three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA), and constructive interference at steady state (CISS-MR) sequences. The clinical and imaging data was compared between HFS with and without NVC. Results: Amongst 162 consecutive HFS patients, 2 (1.6%) had bilateral symptoms. Both patients had unilateral onset followed by bilateral and asynchronous facial contractions. The contralateral side of the face began to twitch at a mean of 1.5 years later. MRI/A revealed significant NVC of the root exit zone (REZ) of the facial nerve on the ipsilateral side with mild NVC contralaterally. The degree of NVC correlated with the clinical severity of the patients' symptoms. MRI/A analysis of 40 HFS patients with unilateral symptoms demonstrated NVC on the contralateral side in six patients (15%). The mean age and duration of symptoms were not different between HFS patients with and without contralateral NVC. Conclusions: We demonstrated clinico-radiologic correlation between the clinical severity and the degree of NVC at the REZ of the facial nerve in bilateral HFS. Amongst unilateral HFS, there was no significant difference clinically between those with and without contralateral NVC. The low 1.6% prevalence of bilateral HFS in our Asian cohort was compatible with the rare prevalence in other ethnic populations.

OBJECTIVE:The microbiota-gut-brain axis is a key pathway perturbed by prolonged stressors to produce brain and behavioral disorders. Frontline healthcare workers (FHWs) fighting against COVID-19 typically experience stressful event sequences and manifest some mental symptoms; however, the role of gut microbiota in such stress-induced mental problems remains unclear. We investigated the association between the psychological stress of FHW and gut microbiota.METHODS:We used full-length 16S rRNA gene sequencing to characterize the longitudinal changes in gut microbiota and investigated the impact of microbial changes on FHWs' mental status.RESULTS:Stressful events induced significant depression, anxiety, and stress in FHWs and disrupted the gut microbiome; gut dysbiosis persisted for at least half a year. Different microbes followed discrete trajectories during the half-year of follow-up. Microbes associated with mental health were mainly Faecalibacterium spp. and [Eubacterium] eligens group spp. with anti-inflammatory effects. Of note, the prediction model indicated that low abundance of [Eubacterium] hallii group uncultured bacterium and high abundance of Bacteroides eggerthii at Day 0 (immediately after the two-month frontline work) were significant determinants of the reappearance of post-traumatic stress symptoms in FHWs.LIMITATIONS:The lack of metabolomic evidence and animal experiments result in the unclear mechanism of gut dysbiosis-related stress symptoms.CONCLUSION:The stressful event sequences of fighting against COVID-19 induce characteristic longitudinal changes in gut microbiota, which underlies dynamic mental state changes.

Background Observational studies have found an association between visceral adiposity and stroke. Aims The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue accumulation on stroke and its subtypes. Methods In this two-sample Mendelian randomization study, genetic variants (221 single nucleotide polymorphisms; P < 5 × 10−8) using as instrumental variables for Mendelian randomization analysis was obtained from a genome-wide association study of visceral adipose tissue. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). Mendelian randomization standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analyses (Mendelian randomization-Egger, weighted median, Mendelian randomization-pleiotropy residual sum and outlier) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable Mendelian randomization analysis was employed to adjust potential confounders. Results In the standard Mendelian randomization analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio (OR) 1.30; 95% confidence interval (CI) 1.21–1.41, P = 1.48× 10−11), ischemic stroke (OR 1.30; 95% CI 1.20–1.41, P = 4.01 × 10−10) and large artery stroke (OR 1.49; 95% CI 1.22–1.83, P = 1.16 × 10−4). The significant association was also found in sensitivity analysis and multi-variable Mendelian randomization analysis. Conclusions Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

Pristane-induced arthritis (PIA) could be adoptively transferred by splenic T cells in rats, and innate immunity should play critical roles in T cell activation. However, in pre-clinical stage, the activation mechanism of innate cells like macrophages remains unclear. Here we found that PIA was dependent on macrophages since cell depletion alleviated disease severity. Splenic macrophages of PIA rats showed M1 phenotypic shifting. The quantitative proteomics analysis suggested that macrophages initiated metabolic reprogramming with the conversion of aerobic oxidation to glycolysis in response to pristane in vivo. Notably, macrophages treated with pristane showed mitochondrial dysregulation and increased glycolysis flux and enzyme activity. Additionally, TNFα production, strongly associating with the glycolysis enzyme Ldha/Ldhb, could be reduced as glycolysis was inhibited or be enhanced as citrate cycle was blocked. This work provides detailed insights into the molecular mechanisms of pristane-mediated metabolic reprogramming in macrophages and suggests a new therapeutic strategy for arthritic disorders.

Abstract Introduction Birth parameters have long been reported to have a role in human intelligence. However, the causalities reported in previous observational studies were controversial. Our study aims to provide an unbiased investigation of the causal associations between birth parameters and human intelligence using the Mendelian randomization (MR) approach. Methods Genetic instrumental variables for MR analyses were extracted from large genome‐wide association studies of infant head circumference (N = 10,768), birth length (N = 28,489), and birth weight (N = 321,223). Data for intelligence were obtained from a meta‐analysis of genome‐wide association studies of 269,867 individuals of the European ancestry. Primary MR analysis was performed using the standard inverse‐variance weighted method, and sensitivity analyses were performed using the weighted median, MR‐Egger, and MR‐PRESSO methods. Results Using 10 single nucleotide polymorphisms as instrumental variables, we found that 1 standard deviation increase in infant head circumference was associated with 0.14‐fold higher scores in intelligence tests (β = 0.14, 95% confidence interval: 0.09 to 0.18, PIVW=2.05 × 10–9). The causal relationship was robust when sensitivity analyses were performed. However, birth length and birth weight had no significant associations with intelligence. Conclusion Our findings suggested infant head circumference, but not birth weight and length were associated with intelligence, which might indicate that brain development rather than general fetal growth was responsible for the development of intelligence.

Object:This study aims to compare the efficacy, acceptability and tolerability of cognitive behavior therapy (CBT), pharmacotherapy, and their combination therapy for acute panic disorder via network Meta-analysis.Methods:Electronic databases including PubMed, Web of Science, Embase, Cochrane Library, CNKI, and Wanfang Data were searched for relevant randomized controlled clinical trials from their inception up to March 24, 2021. The outcomes were efficacy (remission rate and response rate), acceptability and tolerability. Network Meta-analysis was adopted with random effects, and estimated relative risk (RR) for all effects of CBT, CBT plus medications, selective serotonin-reuptake inhibitors(SSRIs), serotonin-noradrenaline-reuptake inhibitors(SNRIs), tricyclic antidepressants(TCAs), monoamine oxidase inhibitors(MAOI), benzodiazepines(BZD), noradrenergic-reuptake inhibitors(NRI), and others. This study used gemtc package in R for network analysis, Review Manager for quality assessment, and GRADEPro for evidence assessment, respectively.Results:Identified citations (7 173) included 72 trials comprising 12 293 patients. The treatment measures with higher remission rate and response rate than placebo included CBT+drug( RR:2.4, 95% CI: 1.7-3.5), CBT( RR:1.8, 95% CI:1.4-2.3), SNRI( RR:1.8, 95% CI:1.5-2.2), BZD( RR:1.6, 95% CI:1.4-1.9), SSRI( RR:1.5, 95% CI:1.4-1.7), TCA( RR:1.5, 95% CI: 1.4-1.8)(remission rate in brackets); Among them, CBT combined with medications was better than SSRI, SNRI and TCA. The acceptability of BZD was better than placebo but its tolerability was inferior. Besides, the tolerability of SSRI and TCA was inferior to placebo. Conclusions:CBT combined with medications is more effective than BZD alone and the antidepressants alone. CBT combined with medications may selected the first-line treatment for panic disorder.

Among all psychiatric disorders, anorexia nervosa (AN) has the highest mortality rate. However, there is still no pharmacological therapy for AN. The human plasma proteome may be a great cornerstone for the development of new drugs against AN. Here we performed a Mendelian randomization (MR) analysis to identify causal risk proteins for AN. Exposure data were extracted from a large genome-wide association study (GWAS) of 2994 plasma proteins in 3301 subjects of European descent, while outcome data were obtained from another GWAS of AN (16,992 cases and 55,525 controls of European descent). MR analyses were performed using the inverse-variance weighted (IVW) method and other sensitivity analysis methods. Using single nucleotide polymorphisms as instruments, this study suggested that high TXNDC12 levels were associated with a higher risk of AN (IVW Odd's ratio [OR]: 1.12; 95% confidence interval [CI]: 1.08-1.16; P = 2.35 x 10(-10)), while another protein ADH1B showed the opposite effect (IVW OR: 0.89; 95% CI: 0.85-0.93; P = 2.99 x 10(-7)). The causal associations were robust in multivariable models, genome-wide significant models, and with additional MR methods. No pleiotropy was observed. Our findings suggest that TXNDC12 was associated with a high risk of AN, while AHD1B was associated with a low risk of AN. They might both have implications in AN by regulating the brain dopamine reward system. In combination with existing knowledge on AN, these proteins may be novel drug targets for AN treatment.

Evidence suggests that complex interactions between the immune system and brain have important etiological and therapeutic implications in schizophrenia. However, the detailed cellular and molecular basis of immune dysfunction in schizophrenia remains poorly characterized. To better understand the immune changes and molecular pathways, we systemically compared the cytokine responses of peripheral blood mononuclear cells (PBMCs) derived from patients with schizophrenia and controls against bacterial, fungal, and purified microbial ligands, and identified aberrant cytokine response patterns to various pathogens, as well as reduced cytokine production after stimulation with muramyl dipeptide (MDP) in schizophrenia. Subsequently, we performed single-cell RNA sequencing on unstimulated and stimulated PBMCs from patients and controls and revealed widespread suppression of antiviral and inflammatory programs as well as impaired chemokine/cytokine–receptor interaction networks in various immune cell subpopulations of schizophrenic patients after MDP stimulation. Moreover, serum MDP levels were elevated in these patients and correlated with the course of the disease, suggesting increased bacterial translocation along with disease progression. In vitro assays revealed that MDP pretreatment altered the functional response of normal PBMCs to its re-stimulation, which partially recapitulated the impaired immune function in schizophrenia. In conclusion, we delineated the molecular and cellular landscape of impaired immune function in schizophrenia, and proposed a mutual interplay between innate immune impairment, reduced pathogen clearance, increased MDP translocation along schizophrenia development, and blunted innate immune response. These findings provide new insights into the pathogenic mechanisms that drive systemic immune activation, neuroinflammation, and brain abnormalities in schizophrenia.

Intelligence predicts important life and health outcomes, but the biological mechanisms underlying differences in intelligence are not yet understood. The use of genetically determined metabotypes (GDMs) to understand the role of genetic and environmental factors, and their interactions, in human complex traits has been recently proposed. However, this strategy has not been applied to human intelligence. Here we implemented a two-sample Mendelian randomization (MR) analysis using GDMs to assess the causal relationships between genetically determined metabolites and human intelligence. The standard inverse-variance weighted (IVW) method was used for the primary MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Using 25 genetic variants as instrumental variables (IVs), our study found that 5-oxoproline was associated with better performance in human intelligence tests (P IVW = 9 · 25×10 -5 ). The causal relationship was robust when sensitivity analyses were applied (P MR-Egger = 0 · 0001, P Weighted median = 6 · 29×10 -6 , P MR-PRESSO = 0 · 0007), and no evidence of horizontal pleiotropy was observed. Similarly, also dihomo-linoleate (20:2n6) and p-acetamidophenylglucuronide showed robust association with intelligence. Our study provides novel insight by integrating genomics and metabolomics to estimate causal effects of genetically determined metabolites on human intelligence, which help to understanding of the biological mechanisms related to human intelligence.

To compare 22 oral drugs, cognitive behavior therapy (CBT), and their combination treatments for the acute treatment of adults with panic disorder in terms of remission rate and acceptability.Systematic review and network meta-analysisPubMed, Web of Science, Cochrane Central Register of Controlled Trials, and Embase databases from their inception up to May 26, 2019.Randomized controlled clinical trials (RCTs) of any oral drugs, CBT, CBT combined with any drug, or placebo in the acute treatment of adults with panic disorder diagnosed according to standard operationalized criteria. The primary outcomes were efficacy (remission rate) and acceptability (treatment discontinuations due to any cause).We identified 6585 reports that included 68 full-text RCTs involving 11101 patients. In terms of efficacy, 13 (68%) of 19 interventions were associated with higher remission rates than those of for placebo, with ORs ranging from 2.1 (95% credible interval [CrI] = 1.1 to 4.0) for sertraline to 13 (CrI = 4.5 to 44) for CBT combined with any drug. Regarding acceptability, alprazolam, imipramine, and etizolam were associated with lower dropout rates, with ORs ranging from 0.23 (CrI = 0.15 to 0.33) for alprazolam to 0.076 (CrI = 0.0021 to 0.77) for etizolam. Most of the differences between the other interventions were unclear. In head-to-head analyses, CBT combined with any drug was more effective than the other interventions, but it was no associated with an improvement in acceptability (OR = 0.12 to 0.219).CBT combined with any drug was more effective than the other interventions analyzed in this study. CBT alone did not differ significantly from other drugs alone. We found that most drugs are effective against panic disorder, but they exhibit different acceptability and tolerability profiles.Some randomized controlled trials indicated that combined therapy are more effective than drug alone or cognitive behavior therapy alone. Nevertheless, drug monotherapy, cognitive behavior therapy, and combination therapy had never been compared in a comprehensive network meta-analysis. With this evidence gap remaining, the availability of reliable evidence of the relative merits of multiple interventions is essential to ensuring that clinicians choose the best option for each individual patient.This network meta-analysis is the first to evaluate the relative merits of cognitive behavior therapy, cognitive behavior therapy combined with any drug, and 22 oral drugs in the field of panic disorder. The results showed a significant higher remission rates for cognitive behavior therapy combined with any drug than those of the other interventions. Cognitive behavior therapy alone was superior to placebo but did not differ significantly from other active drugs. Additionally, paroxetine, venlafaxine, fluoxetine, sertraline, and clonazepam are more recommendable than the other drugs based on their remission rates, scores on panic-symptoms scales, and acceptability.

ABSTRACTObjectiveGut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia.DesignGut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse.ResultsBoth microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors.Conclusionmicrobiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia.SummarySignificance of this studyWhat is already known about this subject?➢ Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA).➢Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms.➢Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters.What are the new findings?➢Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients.➢A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls.➢Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling.➢SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA.How might it impact on clinical practice in the foreseeable future?➢Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia.➢Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy.