OBJECTIVE:Major Depressive Disorder (MDD) with atypical features, briefly named Atypical Depression (AFD), exhibits affective instability and metabolic-immune abnormalities, yet objective biomarkers remain lacking. This exploratory longitudinal pilot study aimed to evaluate whether plasma proteomic and metabolomic profiling could nominate candidate immune-metabolic signatures associated with AFD. METHODS:This longitudinal pilot study included five female AFD patients assessed at baseline, 3 months, and 1 year, and five healthy female controls assessed at baseline. Plasma samples were collected at predefined time points for SomaScan®-based proteomic profiling and UHPLC-QTOF-MS-based untargeted metabolomic profiling. Ensemble Feature Selection (EFS), co-expression network analysis (WGCNA), and multi-omics integration (O2PLS, correlation) were applied to identify immuno-metabolic signatures associated with affective instability. RESULTS:EFS nominated candidate proteins (e.g., IFN-λ1, PIAS4, CD63) and metabolites (e.g., glutamic acid, uric acid, stearic acid) involved in immune response and oxidative stress as prioritized features in AFD. WGCNA clustered 19 proteomic modules, with at least eight enriched for immune/inflammatory pathways. The salmon module, associated with innate immunity, showed a nominal inverse Pearson correlation with stearic acid (r = -0.55, p = 0.01). Cross-omics analysis further suggested shared proteomic-metabolomic covariance, and focused analysis showed an inverse PIAS4-stearic acid pattern in the joint latent space. DISCUSSION:The findings suggest that AFD may involve dynamic immune-metabolic alterations. The longitudinal design indicates that these molecular changes may evolve over time rather than represent fixed abnormalities, potentially reflecting ongoing interactions between inflammatory processes and metabolic regulation. Notably, the exploratory inverse relationship between stearic acid and a PIAS4-centered immune module points to a potential link between lipid metabolism and innate immune activity. Based on these multi-omics observations and prior literature, it was hypothesized that immune-lipid interactions may contribute to mood instability in AFD. CONCLUSION:The exploratory longitudinal pilot study nominates PIAS4-centered immuno-metabolic signals as candidate molecular features of AFD. The findings support the potential utility of longitudinal multi-omics for mapping dynamic biomarker networks in affective disorders. However, larger, independent, medication-informed, and demographically diverse cohorts are required to validate these candidate signatures and clarify their relevance to diagnosis, treatment response, and disease-course monitoring.

Introduction While mitochondrial dysfunction is implicated in schizophrenia, comprehensive understanding of mitochondrial lipid dysregulation in disease pathogenesis remains limited. Objectives To elucidate lipid-driven mitochondrial pathology in schizophrenia and developing nutritional interventions to ameliorate cognitive impairment in schizophrenia through mitochondrial lipid homeostasis restoration. Methods Here, this study investigated a total of 93 schizophrenia patients (61.3% male) and 34 matched healthy controls (41.2% male). Comprehensive mitochondrial lipidomic analyses using ultrahigh performance liquid chromatography-mass spectrometry were conducted to characterize pathological alterations in patients. Building on identification of arachidonic acid (AA) deficiency in schizophrenia-related cognitive impairment, we conducted a six-week nutritional intervention to evaluate AA supplementation’s therapeutic potential. Integrated mitochondrial lipidomic and transcriptomic profiling was performed to explore AA intervention-induced molecular changes and underlying mechanisms. Results Comparative analyses demonstrated significantly perturbed mitochondrial lipid profiles in schizophrenia patients, characterized by elevated oxidized lipids and AA deficiency. These metabolic disturbances exhibited strong positive correlations with cognitive impairment severity. Six-week AA supplementation improved cognitive performance through enhanced reaction speed, increased memory accuracy, and reduced decision-making errors. Concurrently, AA intervention restored mitochondrial lipid homeostasis by eliminating excessive levels of oxidative lipids. Enrichment analysis highlights key molecular pathways changed in mitophagy and ROS-induced ferroptosis. Conclusion Our study identifies mitochondrial lipid dyshomeostasis as a pathological hallmark in schizophrenia and clarifies that AA supplementation may restore lipid balance, alongside with coordinating activation of mitophagy and ferroptosis suppression. These molecular corrections underlie the clinical efficacy of cognitive improvements, positioning mitochondrial lipid modulation as a promising therapeutic strategy for schizophrenia.

The psychological well-being of college students is a growing concern due to its impact on personal and academic outcomes. Traditional symptom-based scales for psychological health screening are often subjective and prone to misclassification. The niacin skin flushing response (NSFR), a physiologically grounded biomarker, has shown promise in identifying psychiatric conditions. This study explored the application of NSFR as an objective tool for psychological health screening among college students. We recruited 633 college freshmen who completed the “College Student Mental Health Crisis Intervention Scale” and underwent the NSFR test. Students identified as at-risk by the scale (n = 191) were further evaluated by psychological counselors and classified as “Counselor-Assessed Normal” (CA-Normal, n = 164) or “Counselor-Assessed AtRisk” (CA-AtRisk, n = 27). NSFR responses, including flushing area and EC50 values, were compared between groups using multiple linear regression models adjusted for covariates. Logistic regression and ROC analysis were employed to assess the discriminative efficacy of NSFR. CA-AtRisk students exhibited blunted NSFR, with significantly higher EC50 values (p = 0.017) and smaller flushing areas at 4, 5, 7, and 8 min (p < 0.05) compared to CA-Normal students. The sum of flushing scores at 4 min with 60 mM AMN demonstrated the best discrimination efficiency (sensitivity = 0.444, specificity = 0.829). Combining NSFR with the scale doubled the positive predictive value (PPV) from 0.141 to 0.300. NSFR shows potential as an objective adjunct tool for psychological health screening in college students, improving the accuracy of risk identification. Its integration into screening protocols could optimize resource allocation, particularly in settings with limited psychological health services. Further research is needed to validate these findings in larger and more diverse populations.

Background:Mood disorders (MDs), including depressive disorder (DD) and bipolar disorder (BD), represent a major global health burden, yet the absence of objective biomarkers has persistently hindered their accurate clinical diagnosis. The niacin skin flushing response (NSFR) has shown promise as a potential biomarker; however, inconsistencies in diagnostic efficacy and response characteristics across studies have limited its utility. This meta-analysis aims to systematically evaluate the NSFR in MD patients to address these discrepancies. Methods:A comprehensive search of PubMed, Embase, Cochrane Library, and Scopus databases was conducted for articles published through May 2025, identifying 18 eligible case-control studies involving 1848 participants (888 MD patients and 960 HC). Random-effects models were used to assess the degree, speed, and sensitivity of NSFR, while subgroup analyses and meta-regression explored potential sources of heterogeneity. Results:MD patients exhibited markedly blunted NSFR, characterized by reduced degree and speed of response (standardized mean difference [SMD] = -0.59, 95% confidence interval [CI]: [-1.12; -0.05] and SMD = 0.72, 95% CI: [0.35; 1.10]), while no statistically significant difference in NSFR sensitivity was observed (SMD = 0.51, 95% CI: [-0.18; 1.20]). Subgroup analyses identified substantial heterogeneity across detection methods, geographical regions, and control sources, highlighting the need for standardized protocols. Meta-regression analyses indicated that sample size, publication year, gender distribution, and age did not significantly affect outcomes, further strengthening the robustness of our findings. Conclusion:This study reinforces the potential of NSFR as a biomarker for MD and highlights the critical need to address heterogeneity through standardized methodologies in future research to enhance its diagnostic reliability.

BACKGROUND AND HYPOTHESIS:The multifactorial pathogenesis of schizophrenia (SZ) hinders the diagnosis and treatment of this disorder. Niacin skin flushing response (NSFR) has been identified as an endophenotype for SZ, but the proportion of blunted NSFR (BNR) varied between studies. This study aims to clarify the relationship between NSFR and SZ through a meta-analysis. STUDY DESIGN:PubMed, Embase, Web of Science, Cochrane, and Scopus databases were searched for articles published until May 2024, and 32 studies were eligible. Using random-effects models, we examined the characteristics of NSFR in SZ, including the reaction degree, speed, sensitivity, and risk and prevalence of BNR. Subgroup analyses and regression analyses were performed to investigate the relevant effect factors of NSFR. STUDY RESULTS:The reaction degree (SMD = -0.90; CI, -1.08 to -0.72), speed (SMD = 0.64; CI, 0.02-1.25), and sensitivity (SMD = 0.89; CI, 0.49-1.29) of NSFR was significantly reduced in SZ compared to healthy controls (HC). Moreover, we observed a positive association between BNR and SZ (OR = 8.50; CI, 5.93-12.19). The overall prevalence of BNR was 58.5% in SZ (CI, 49.3%-67.8%) compared to 11.8% in HC (CI, 7.7%-15.9%). In addition, NSFR detection method, geographical regions, and age were found to have effects on reaction degree and prevalence of BNR. CONCLUSIONS:This study confirmed a significantly abnormal NSFR and higher prevalence of BNR in SZ, which highlights the potential facilitation of the diagnosis and personalized intervention of SZ subgroups. In addition, the study points to a need to establish a standardized method for NSFR assessment.

Background and Hypothesis:Mitochondrial dysfunction is increasingly implicated in schizophrenia (SZ) pathogenesis. To maintain mitochondrial homeostasis under cellular stress, a sophisticated mitochondrial quality control (MQC) mechanism has developed, encompassing mitochondrial biogenesis, dynamics, and mitophagy. Study Design:This study systematically evaluated MQC in peripheral leukocytes of 42 SZ patients and 43 healthy controls through morphological analysis, MQC gene expressions, mitochondrial DNA (mtDNA) maintenance, and oxidative damage. Besides, we validated the regulatory effects of oxidative stress on MQC in vitro using a neuronal model treated with hydrogen peroxide. Study Results:We observed mitochondrial fragmentation in SZ, characterized by increased organelle numbers with reduced sizes. This was supported by imbalanced MQC, with expression of biogenesis-related genes SIRT1 and TFAM upregulated (P = .008 and 0.027, respectively), and mitophagy receptor gene PHB2 suppressed (P = .041), indicating enhanced biogenesis but impaired mitophagy. Despite enhanced biogenesis, mtDNA copy number was lower (P < .001) with more oxidative damage (P = .037). Furthermore, we discovered deficits in antioxidant capacity, including reduced coenzyme Q10 levels and superoxide dismutase (SOD) activity, with SOD decline correlating with mtDNA depletion. This suggests redox imbalance contributes to MQC dysregulation, supported by findings from an oxidation-damaged neuronal model. Moreover, disrupted MQC functionally impaired energy metabolism, reflected by downregulated NDUFV1 expression (P = .031) and increased lactate-to-pyruvate ratios (P < .001). Conclusions:Our findings demonstrated MQC imbalance in SZ, manifested as mitochondrial fragmentation and mtDNA depletion, probably resulted from oxidative damage. These disruptions may underlie the energy metabolism abnormalities in SZ.

BACKGROUND:Findings regarding the efficacy of n-3 polyunsaturated fatty acid (PUFA) supplementation as an adjunct treatment for schizophrenia (SZ) have been inconsistent. This study investigated whether n-3 PUFA supplementation was associated with changes in niacin skin flush response (NSFR) and clinical symptoms in patients with SZ, and explored the value of baseline NSFR for patient stratification. METHODS:A total of 99 patients with SZ and 30 healthy controls (HCs) were enrolled. Patients with SZ were randomized in a 1:2 ratio to standard pharmacotherapy alone or standard pharmacotherapy plus n-3 PUFA supplementation for 21 days. NSFR and Positive and Negative Syndrome Scale (PANSS) assessments were performed at baseline and post-intervention. RESULTS:Patients with SZ showed significantly lower baseline NSFR than HCs (P = 7.097 × 10-6). Following intervention, total PANSS scores decreased in both groups, while significant NSFR improvement was observed only in the n-3 PUFA supplementation group. Adjusted linear mixed-effects models revealed a significant "group × time" interaction for NSFR (standardized β = 0.57, 95% CI: 0.08 to 1.06, P = 0.025). Exploratory stratified analysis showed that patients with blunted baseline NSFR who received n-3 PUFA supplementation exhibited the most favorable short-term response, reflected by the largest and statistically significant NSFR increase, with a directionally favorable change in PANSS total score. CONCLUSIONS:Baseline NSFR blunting may help identify a subgroup of SZ patients with greater short-term responsiveness to adjunctive n-3 PUFA supplementation. These findings support further investigation of NSFR as a candidate stratification marker for targeted adjunctive intervention in schizophrenia.

BACKGROUND:Membrane lipids play a crucial role in brain function and cell signalling, and they serve as key biological substrates in inflammatory responses, thrombosis, and energy metabolism. Multiple clinical and molecular evidences suggest that membrane lipids are probably involved in the pathogenesis of ischemic stroke (IS). However, current knowledge about the membrane lipid landscape and its involvement in IS pathophysiology is limited. METHODS:We performed untargeted lipidomic analysis on erythrocyte membranes from 56 IS patients and 55 healthy controls. Integrated with gene expression and weighted gene co-expression network analysis, we identified dysregulated lipid signalling pathways and their contributions to IS pathophysiology. RESULTS:A total of 1392 erythrocyte membrane lipids were detected and quantified. Our results revealed significant impairment of membrane lipid homeostasis in IS patients, characterized by a marked reduction in glycerophospholipids (GPLs) and lysophospholipids (LPLs). Further analysis indicated that the impaired lipids were primarily concentrated in three disturbed signalling pathways, including the phospholipase A2-mediated GPL-LPL pathway, the phospholipase C-mediated inositol 1,4,5-trisphosphate/diglyceride pathway, and the sphingosine-1-phosphate (S1P)-S1P receptors pathway. Gene expression results indicated that these pathways were inhibited during the subacute phase of IS. Furthermore, these lipid signalling pathways form a highly interconnected network that collaboratively contributes to inflammation and thrombosis in IS, thereby influencing the progression and prognosis of the disease. CONCLUSION:Our findings reveal impaired erythrocyte membrane lipid homeostasis in IS, which implicates inflammatory processes and thrombosis in IS. This research offers new insights into the role of membrane lipids in IS pathogenesis, potentially informing future monitoring and therapeutic strategies.

Adolescent depression is a significant global health challenge, with many patients responding inadequately to antidepressant treatments. Omega-3 polyunsaturated fatty acids (ω3 PUFAs) have been proposed as a potential adjunctive treatment, but their precise mechanisms remain poorly understood. This study aimed to explore the mechanisms through which ω3 PUFAs exert their antidepressant effects and to identify potential biomarkers for their therapeutic response. A comprehensive assessment of plasma metabolomic and erythrocyte membrane lipidomic was performed on 51 depressed adolescents who were randomly assigned to received either ω3 PUFAs plus paroxetine (n = 27) or paroxetine alone (n = 24) for 12 weeks. Following ω3 PUFA supplementation, phospholipid metabolism emerged as the most significantly altered pathway. ω3 PUFAs markedly influenced the composition of membrane fatty acids, significantly increasing the ω3 PUFA content, decreasing the ω6/ω3 PUFA ratio, and increasing membrane fluidity. Notably, ω3 PUFAs reduced lipid peroxidation in both plasma and cell membranes while enhancing antioxidant capacity in the membranes. Moreover, alterations in phospholipids and membrane function were significantly correlated with improvements in depressive symptoms and cognitive function. Importantly, ω3 PUFA supplementation resulted in greater improvement in clinical symptoms compared to the non-supplemented group exclusively in the subgroup with high baseline oxidative damage levels. This study suggests that ω3 PUFAs promoted phospholipid integration and alleviated oxidative stress, which may account for their antidepressant effects. Lipid oxidation biomarkers could help identify patients likely to benefit from ω3 PUFA supplementation. These findings advance our understanding of the mechanism and clinical application of ω3 PUFAs in treating adolescent depression.

Postpartum depression (PPD) affects maternal mental health extensively and is challenged by the lack of objective diagnostic methods. This study aimed to explore the characteristics of niacin skin flush response, a diagnostic marker for depression, in individuals with PPD and to determine its clinical potential as an adjunctive screening marker. A total of 1417 parturients was recruited in this study. Edinburgh Postnatal Depression Scale was used to screen for depression with a cut-off score ≥ 13. The Patient Health Questionnaire-9 scale was used to test the consistency of scale screening. The Chi-square test was used to compare the screening results of the two scales, and the reliability and validity of the two scales were discussed. Mann Whitney U test was used to analyze the differences in niacin-flushing between PPD and healthy controls (HC), and a ten-fold cross-validation with logistic regression was used to verify the potential of niacin-flushing to distinguish between PPD and HC. A screening model for women with PPD was established by bivariate truncation method. The results of the two depression screening scales were 12.85

BACKGROUND:Niacin Skin-Flushing Response (NSR) has emerged as a promising objective biomarker for the precise diagnosis of mental disorders. However, its diagnostic potential has been constrained by the limitations of traditional statistical approaches. The advent of Artificial Intelligence (AI) offers a transformative opportunity to overcome these challenges. This study presents a novel contribution to the field by establishing an open-access dataset and developing advanced AI-driven tools to enhance the diagnostic accuracy of psychiatric disorders through NSR analysis. METHODS:This study introduces the world's first open dataset specifically developed for AI studies of Niacin Skin-Flushing Response (NSR), a physiological biomarker associated with mental illnesses including depression, bipolar disorder, and schizophrenia. Leveraging this dataset, we developed an advanced Machine Learning (ML) approach designed for the broad diagnosis of mental disorders. Distinct from prior studies which are often limited to First Episode Schizophrenia and depend on specific devices, our approach champions device independence. The core of our methodology involves a novel algorithm featuring an Efficient-Unet based Deep Learning model for the precise segmentation of NSR areas. This segmentation is significantly enhanced by runtime data augmentation and trained on a robust train/validation/test dataset split. Subsequently, a Support Vector Machine (SVM) method is employed for psychiatric disorder classification utilizing feature vectors extracted from the segmentation of NSR areas with a 3-scale quantization. The SVM training incorporates 5-fold cross-validation, Synthetic Minority Over-sampling Technique (SMOTE) for managing class imbalance, and hyperparameter tuning to optimize balanced accuracy. RESULTS:The established dataset comprises 600 high-quality NSR images from 120 individuals, encompassing a diverse cohort of healthy controls and patients with various mental illnesses. The developed AI tools offer an objective, swift, and highly accurate approach that is demonstrably independent of the diagnosed condition or the specific device used for image acquisition. Comparative results demonstrate that the ML-based diagnostic approach achieves a sensitivity ranging from 60.0 to 65.0% and a specificity from 75.0 to 88.3% across various types of illnesses, further underscoring its broad applicability and device independence. CONCLUSIONS:This research conclusively demonstrates the significant potential of advanced AI tools in achieving precise diagnosis of psychiatric disorders, potentially surpassing human capabilities in both speed and accuracy. With the provision of the proposed open dataset and the introduction of novel methodologies, this study marks substantial progress in developing an objective and accurate NSR-based screening process for a wide spectrum of psychiatric disorders. Its enhanced applicability and independence from specific devices hold profound potential to substantially advance mental health diagnostics and contribute to improved patient outcomes globally.

AIMS:The diagnosis of diabetic peripheral neuropathy (DPN) remains challenging because of the lack of objective biomarkers. In this study, we explored the niacin-induced skin flushing response (NSFR) as a novel diagnostic biomarker for DPN on the basis of its association with microangiopathy. MATERIALS AND METHODS:We recruited 114 patients with type 2 diabetes (51 with DPN, 59 without DPN, and 4 with unclear neuropathy status) and 91 healthy controls. Peripheral neuropathy was assessed through clinical symptoms and signs, vibration threshold testing and electromyography. NSFR was measured using a six-chamber sandwich patch and six concentrations of aqueous methyl nicotinate. Demographic and clinical data were collected via questionnaires and medical records. RESULTS:The NSFR was significantly lower in patients with type 2 diabetes than in healthy controls (1613 ± 1130.1 vs. 2494.6 ± 1071.9, p < 0.001) and was further reduced in DPN patients than in those without DPN (1105.4 ± 950.93 vs. 2063.7 ± 1119.3, p < 0.001). The association between the NSFR and the risk of developing DPN remained significant after adjusting for potential confounding factors (OR 0.848, 95% CI 0.757-0.949; p = 0.004). A nomogram illustrated the role of the NSFR in predicting DPN occurrence. The ROC curve for the NSFR had an AUC of 0.740, with 72.55% sensitivity and 66.10% specificity. For the combined model, the AUC improved to 0.898, with 89.58% sensitivity and 78.85% specificity. Decision curve analysis confirmed the practical clinical value of the NSFR for predicting DPN risk. CONCLUSIONS:NSFR is significantly associated with the risk of developing peripheral neuropathy in diabetic patients and shows promise as a diagnostic tool for DPN.

Adolescent depression is a globally concerned mental health issue, the pathophysiological mechanisms of which remain elusive. Membrane lipids play a crucial role in brain development and function, potentially serving as a crossroad for the abnormalities in neurotransmitters, neuroendocrine, inflammation, oxidative stress, and energy metabolism observed in depressed adolescents. The primary aim of this study was to investigate the erythrocyte membrane lipid profile in adolescent depression. A total of 2838 erythrocyte membrane lipids were detected and quantified in 81 adolescents with depression and 67 matched healthy adolescents using ultra-high performance liquid chromatography-mass spectrometry. Depressed adolescents exhibited significantly different membrane lipid characteristics compared to healthy controls. Specifically, the levels of cholesterol, sphingomyelins, and ceramides were increased, while ether lipids were decreased in patients. Moreover, the patients showed reduced polyunsaturated fatty acids and elevated lipophilic index in membrane, suggesting diminished membrane fluidity. The higher oxidized membrane lipids and plasma malondialdehyde were observed in adolescent depression, indicating the presence of oxidative stress. Importantly, membrane lipid damage was associated with more severe depressive symptoms and worse cognitive function in patients. In addition, reduced polyunsaturated fatty acids and membrane fluidity may be partly responsible for the blunted niacin skin flushing response found in depressed adolescents. In conclusion, our results reveal impaired erythrocyte membrane lipid homeostasis in adolescents with depression, which may implicate membrane dysfunction in the brain. These findings offer new insights into the underlying molecular mechanisms of adolescent depression, highlighting the potential of counteracting membrane damage as a promising avenue for future therapeutic interventions.

Many psychiatric disorders are associated with major cognitive deficits. However, it is uncertain whether these deficits develop as a result of psychiatric disorders and what shared risk factors might mediate this relationship. Here, we utilized the Mendelian randomization (MR) analysis to investigate the complex causal relationship between nine major psychiatric disorders and three cognitive phenotypes, while also examining the potential mediating role of oxidative stress as a shared biological underpinning. Schizophrenia (SZ), major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD) showed a decreasing effect on cognitive performance, intelligence, and education, while bipolar disorder (BPD) increased educational attainment. MR-Clust results exhibit the shared genetic basis between SZ and other psychiatric disorders in relation to cognitive function. Furthermore, when oxidative stress was considered as a potential mediating factor, the associations between SZ and the three dimensions of cognition, as well as between MDD and intelligence and ADHD and intelligence, exhibited larger effect sizes than the overall. Mediation MR analysis also supported the causal effects between psychiatric disorders and cognition via oxidative stress traits, including carotene, vitamin E, bilirubin, and uric acid. Finally, summary-based MR identified 29 potential causal associations of oxidative stress genes with both cognitive performance and psychiatric disorders. Our findings highlight the importance of considering oxidative stress in understanding and potentially treating cognitive impairments associated with psychiatric conditions.

Schizophrenia (SZ) is associated with an increased risk of violence, with clinical diagnosis primarily relies on symptomatology. The niacin skin flushing response (NSFR) is proposed as a potential biomarker for SZ, but its effectiveness in violent offenders with schizophrenia (VOSZ) remains unevaluated. This study investigates whether the diagnostic model differentiating general SZ patients (GSZ) from healthy controls (HCs) using NSFR can also distinguish VOSZ from HCs. SZ patients were continuously sampled based on the International Classification of Diseases, 10th Edition, and categorized into VOSZ (with a history of violent crimes), and GSZ (without such history). HCs had no psychiatric illnesses or violent crime history. A total of 315 VOSZ, 296 GSZ, and 281 HCs were recruited. Least absolute shrinkage and selection operator regression was used to select variables and construct diagnostic models based on NSFR. No significant differences in age, sex or BMI were observed among groups. Both VOSZ and GSZ exhibited similar blunted NSFR compared to HCs. The diagnostic model constructed by 14 NSFR variables distinguishing GSZ from HCs was successfully transferred to distinguish VOSZ from HCs, with areas under the curve of 0.796 (specificity = 81.6%, sensitivity = 64.2%) and 0.798 (specificity = 80.0%, sensitivity = 70.2%), respectively. Moreover, NSFR was unrelated to illness severity, violence, or antipsychotic dosage in VOSZ, suggesting it is a trait indicator of SZ. This study supports the NSFR as an objective diagnostic biomarker for distinguishing VOSZ from HCs, expanding its applicability, although it may not specifically identify violent offenders among SZ patients.

Niacin skin bluntness is a promising biomarker for schizophrenia, especially in precision medicine, as it helps identify a distinct subgroup (around 1/3) of patients with schizophrenia who experience severe functional impairment. However, research has not clarified if this phenotype is just a byproduct of the onset of the disease or is involved in the etiology of schizophrenia. We hypothesize that niacin bluntness reflects causal alterations in schizophrenia. We firstly conducted a quasi-genome-wide association analysis within schizophrenia patients to identify instrumental SNPs for niacin response. Then a two-sample bi-directional Mendelian randomization (MR) analysis was implemented to estimate the potential causal effects between niacin response and schizophrenia. 25 independent SNPs showed a trend of genome-wide significant association with niacin response in schizophrenia. In the MR analysis, the F statistics of the two instrumental SNPs for niacin response is 30.77, indicating a proper strength. As heterogeneity of the SNPs was detected (p<0.05), the result of inverse variance weighted method for multiplicative random effects was adopted for evaluation of the detected causal effect (OR=1.272, p=9.46E-03). In reverse MR analysis, none of the methods supported a causal effect of schizophrenia on niacin response (all p>0.05). Our results revealed that the attenuated niacin response caused schizophrenia but not vice versa. Etiological studies on niacin bluntness in schizophrenia are needed and will pave the way for biomarker-guided personalized treatment in future. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Natural Science Foundation of China (81901354), National Key Research and Development Program of China (2022YFC2703200), Chinese National Programs for Brain Science and Brain-like Intelligence Technology (2021ZD0200800), Wuhu Science and Technology Bureau Science and Technology Achievements Transformation Project (2021cg29) and China Postdoctoral Science Foundation (2018M630442, 2020T130407). ### 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 the WuHu Fourth People's Hospital 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 All data produced in the present study are available upon reasonable request to the authors.

Aim: Blunted niacin response (BNR) was an endophenotype of schizophrenia, but the underlying mechanism remains unclarified. The objective of this study was to verify whether genes associated with BNR pathway constitute the genetic basis and the pathological mechanism of BNR phenotypic psychiatric patients.Methods: Two independent sample sets consisting of 971 subjects were enrolled in this study. A total of 62 variants were genotyped in the discovery set, then the related variants were verified in the verification set. The published PGC GWAS data were used to validate the associations between the variants and psychiatry disorders. RT-PCR analysis, eQTL data, and Dual-Luciferase Reporter experiment were used to investigate the potential molecular mechanisms of the variants underlying BNR.Results: The results showed that two SNPs, rs56959712 in HCAR2 and rs2454721 in HCAR3 were significantly associated with niacin response. The risk allele T of rs2454721 could affect the niacin responses of psychiatric patients through elevated HCAR3 gene expression. These two genes, especially HCAR3, were significantly associated with the risk of schizophrenia, as identified in this study and verified using the published GWAS data.Conclusion: HCAR3 is a novel schizophrenia susceptibility gene which is significantly associated with blunted niacin response in schizophrenia. In-depth investigation of HCAR3 is of great significance for uncovering the pathogenesis and propose new therapeutic targets for psychiatric disorders, especially for the BNR subgroup patients.

Background The etiological research of schizophrenia has long been undermined by its subjective nature of diagnosis and heterogeneity among patients. Searching for objective markers of schizophrenia could assist diagnosis and facilitate precise management. Niacin bluntness, a unique skin feature manifested in niacin flushing test, is one of these biomarkers promising for schizophrenia. The proportion of schizophrenia patients who are with typical niacin bluntness was estimated to be around 25%-33%, which forms a distinctive biological subtype of schizophrenia. Patients with niacin bluntness were featured by more negative symptoms and more severe functional impairment. However, we still don't know whether niacin bluntness is a phenotypic resultant of schizophrenia, or it is or reflects certain causative factors contributing to the onset of the disease. If the latter is true, this phenotype will be much more clinically meaningful. In this study, we used two-directional Mendelian randomization (MR) analysis to estimate causative relationships between niacin flushing status and schizophrenia. Methods 473 patients with schizophrenia were recruited from inpatients at the Fourth People's Hospital of Wuhu in Anhui province of China. The participants' forearm was administrated with niacin patches and photographed. The flush responses were scored by an in-house developed software and rechecked by an experienced researcher. Single nucleotide polymorphism (SNP) genotyping was performed by Illumina Asian Screening Array. The association of every single SNP with overall score of niacin response was tested by linear regression using PLINK, correcting for top five principal-component scores, age and gender.Bidirectional MR analyses were performed in this study. For niacin response, the associated SNPs below a threshold of P < 0.000001 were selected as candidate instrumental variables. For schizophrenia, the summary-level data from a previously published GWAS in East Asian people was used, involving 22778 cases and 35362 controls. R package “TwoSampleMR” was used to implement bidirectional MR estimates. Two SNPs were filtered out and analyzed as the instrumental variables for niacin response and 19 SNPs as the instrumental variables for schizophrenia. Results GWAS revealed two SNPs with a trend of genome-wide significant association (p < 5E-08). In the MR analysis, the F statistics of the two instrumental SNPs for niacin response is 30.77, indicating a proper strength. As heterogeneity of the SNPs was detected (p < 0.05), the result of Inverse variance weighted method for multiplicative random effects was adopted for evaluation of the detected causal effect (OR=1.272, p=9.46E-3). In reverse MR analysis, none of the methods supported a causal effect of schizophrenia on niacin response (all p> 0.05). Discussion The result of this study was in line with previous longitudinal studies, where niacin bluntness has been observed in patients with clinical high risk of psychosis. Our study provides a crucial confirmation on the causal effect of niacin bluntness on schizophrenia. As for the underlying mechanism, though arachidonic acid-GPR109A-prostaglandin pathway has been widely accepted as the biological mechanism underlying skin flushing induced by niacin, we suggest oxidative stress may be the driven factor. More studies are required to delineate this etiology, facilitating precision medicine for this particular subgroup of patients.

Background: Depressive disorder in adolescents is a major health problem with inadequate treatment. Omega-3 (0)3) polyunsaturated fatty acids are a promising adjuvant therapy in adult depression. The primary objective of this study was to investigate the efficacy of adjuvant 0)3 treatment on depressive symptoms in adolescent depression. Secondarily, we explored the effects of 0)3 on cognitive function and memory and niacin skin flushing response (NSFR), as their robust associations with adolescent depression. Methods: A total of 71 adolescents with depression (aged 13-24; 59.2 % female) were randomly assigned to receive 0)3 plus Paxil (n = 34) or Paxil alone (n = 37) for 12 weeks. Primary outcome was depression severity according to scores on Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes were cognitive function and memory, and NSFR. Results: Significant improvements in depressive symptoms over time (p = 0.00027 at week 12) were observed in the 0)3 + Paxil group compared with Paxil group. Additionally, in the 0)3 + Paxil group, significant improvements in memory over time, and greater cognitive function and NSFR were also observed compared with the Paxil group; the NSFR was negatively correlated with MADRS scores at baseline. Limitations: The trial was open label; thus, the outcome measures should be viewed as preliminary since inherent bias in outcomes due to the potential of a placebo effect. Conclusions: Our results demonstrate that adjuvant 0)3 treatment is effective for reducing depressive symptoms as well as improving cognitive function, memory and the NSFR; these results suggest 0)3 is a promising adjuvant treatment for adolescent depression.

Background: Myocardial Infarction (MI) and severe mental disorders (SMDs) are two types of highly prevalent and complex disorders and seem to have a relatively high possibility of mortality. However, the contributions of common and rare genetic variants to their comorbidity arestill unclear. Methods: We conducted a combined genome-wide association study (GWAS) and exome-wide association study (EWAS) approach. Results: Using gene-based and gene-set association analyses based on the results of GWAS, we found the common genetic underpinnings of nine genes (GIGYF2, KCNJ13, PCCB, STAG1, HLA-C, HLA-B, FURIN, FES, and SMG6) and nine pathways significantly shared between MI and SMDs. Through Mendelian randomization analysis, we found that twenty-seven genes were potential causal genes for SMDs and MI. Based on the exome sequencing data of MI and SMDs patients from the UK Biobank, we found that MUC2 was exome-wide significant in the two diseases. The gene-set analyses of the exome-wide association study indicated that pathways related to insulin processing androgen catabolic process and angiotensin receptor binding may be involved in the comorbidity between SMDs and MI. We also found that six candidate genes were reported to interact with known therapeutic drugs based on the drug–gene interaction information in DGIdb. Conclusions: Altogether, this study revealed the overlap of common and rare genetic underpinning between SMDs and MI and may provide useful insights for their mechanism study and therapeutic investigations.