Translational Psychiatry最新文献

{"title":"mPFC DCC coupling with CaMKII⁺ neuronal excitation participates in behavioral despair in male mice.","authors":"Ping Cheng, Keke Ding, Daokang Chen, Chen Yang, Juan Wang, Shaojie Yang, Ming Chen, Guoqi Zhu","doi":"10.1038/s41398-025-03266-x","DOIUrl":"10.1038/s41398-025-03266-x","url":null,"abstract":"<p><p>A longed lack of control over harmful stimuli can lead to learned helplessness (LH), a significant factor in depression. However, the cellular and molecular mechanisms underlying LH, and eventually behavioral despair, remain largely unknown. The deleted in colorectal cancer (dcc) gene is associated with the risk of depression. However, the therapeutic potential and regulation mechanism of DCC in behavioral despair are still uncertain. In this study, we showed that depressive stimulators, including LH, lipopolysaccharide, and unpredictable chronic mild stress, triggered an elevation in DCC expression in the medial prefrontal cortex (mPFC). Additionally, elevated DCC expression in the mPFC was crucial in inducing behavioral despair, as evidenced by the induction of behavioral despair in normal mice and exacerbation of behavioral despair in LH mice upon DCC overexpression. By contrast, neutralizing DCC activity ameliorated LH-induced behavioral despair. Importantly, we elucidated that pathological DCC expression was attributable to the excessive excitation of CaMKII⁺ neurons in a manner dependent on the calpain-mediated degradation of SCOP and aberrant phosphorylation of the ERK signaling pathway. In addition, the increase in DCC expression led to a decreased excitability threshold in CaMKII⁺ neurons in the mPFC, which was supported by the observation that the ligand netrin 1 increased the frequency of action potential firing and of spontaneous excitatory postsynaptic currents in CaMKII⁺ neurons. In conclusion, our data indicate that LH triggers the excessive excitation of CaMKII⁺ neurons and activation of calpain-SCOP/ERK signaling to promote DCC expression, and DCC represents a crucial target for the treatment of LH-induced behavioral despair in male mice.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"52"},"PeriodicalIF":5.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting antipsychotic responsiveness using a machine learning classifier trained on plasma levels of inflammatory markers in schizophrenia.","authors":"Jie Yin Yee, Ser-Xian Phua, Yuen Mei See, Anand Kumar Andiappan, Wilson Wen Bin Goh, Jimmy Lee","doi":"10.1038/s41398-025-03264-z","DOIUrl":"10.1038/s41398-025-03264-z","url":null,"abstract":"<p><p>We apply machine learning techniques to navigate the multifaceted landscape of schizophrenia. Our method entails the development of predictive models, emphasizing peripheral inflammatory biomarkers, which are classified into treatment response subgroups: antipsychotic-responsive, clozapine-responsive, and clozapine-resistant. The cohort comprises 146 schizophrenia patients (49 antipsychotics-responsive, 68 clozapine-responsive, 29 clozapine-resistant) and 49 healthy controls. Protein levels of immune biomarkers were quantified using the Olink Target 96 Inflammation Panel (Olink®, Uppsala, Sweden). To predict labels, a support vector machine (SVM) classifier is trained on the Olink®data matrix and evaluated via leave-one-out cross-validation. Associated protein biomarkers are identified via recursive feature elimination. We constructed three separate predictive models for binary classification: one to discern healthy controls from individuals with schizophrenia (AUC = 0.74), another to differentiate individuals who were responsive to antipsychotics (AUC = 0.88), and a third to distinguish treatment-resistant individuals (AUC = 0.78). Employing machine learning techniques, we identified features capable of distinguishing between treatment response subgroups. In this study, SVM demonstrates the power of machine learning to uncover subtle signals often overlooked by traditional statistics. Unlike t-tests, it handles multiple features simultaneously, capturing complex data relationships. Chosen for simplicity, robustness, and reliance on strong feature sets, its integration with explainable AI techniques like SHapely Additive exPlanations enhances model interpretability, especially for biomarker screening. This study highlights the potential of integrating machine learning techniques in clinical practice. Not only does it deepen our understanding of schizophrenia's heterogeneity, but it also holds promise for enhancing predictive accuracy, thereby facilitating more targeted and effective interventions in the treatment of this complex mental health disorder.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"51"},"PeriodicalIF":5.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alcohol insensitivity and the incentive salience of alcohol: Two decades of work relevant to future directions of the addictions neuroclinical assessment.","authors":"Roberto U Cofresí, Thomas M Piasecki, Bruce D Bartholow","doi":"10.1038/s41398-025-03273-y","DOIUrl":"10.1038/s41398-025-03273-y","url":null,"abstract":"","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"50"},"PeriodicalIF":5.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suicidal risk is associated with hyper-connections in the frontal-parietal network in patients with depression.","authors":"Yanping Ren, Meiling Li, Chunlin Yang, Wei Jiang, Han Wu, Ruiqi Pan, Zekun Yang, Xue Wang, Wei Wang, Wen Wang, Wenqing Jin, Xin Ma, Hesheng Liu, Rena Li","doi":"10.1038/s41398-025-03249-y","DOIUrl":"10.1038/s41398-025-03249-y","url":null,"abstract":"<p><p>Suicide is a complex behavior strongly associated with depression. Despite extensive research, an objective biomarker for evaluating suicide risk precisely and timely is still lacking. Using the precision resting-state fMRI method, we studied 61 depressive patients with suicide ideation (SI) or suicide attempt (SA), and 35 patients without SI to explore functional biomarkers of suicide risk. Among them, 21 participants also completed electroconvulsive therapy (ECT) treatment, allowing the examination of functional changes across different risk states within the same individual. Functional networks were localized in each subject using resting-state fMRI and then an individualized connectome was constructed to represent the subject's functional brain organization. We identified a set of connections that track suicide risk (r = 0.41, p = 0.001) and found that these risk-associated connections were hyper-connected in the frontoparietal network (FPN, p = 0.008, Cohen's d = 0.58) in patients with suicide risk compared to those without. Moreover, ECT treatment significantly reduced (p = 0.001, Cohen's d = 0.56) and normalized these FPN hyper-connections. These findings suggest that connections involving FPN may constitute an important biomarker for evaluating suicide risk and may provide potential targets for interventions such as non-invasive brain stimulation.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"49"},"PeriodicalIF":5.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic profiles link corticostriatal microarchitecture to genetics of neurodevelopment and neuropsychiatric risks.","authors":"Sheng Hu, Yanming Wang, Xiaoxiao Wang, Yang Ji, Chuanfu Li, Bensheng Qiu","doi":"10.1038/s41398-025-03260-3","DOIUrl":"10.1038/s41398-025-03260-3","url":null,"abstract":"<p><p>Many studies on macroscale organization have focused on only the cerebral cortex or striatum, leaving a large gap in the microstructural gradient of corticostriatal covariance. Here, we partitioned the striatum into seven distinct parcels and computed the microstructural covariance between each parcel and the cerebral cortex using T1-weighted/T2-weighted mapping. We found that corticostriatal microstructural covariance exhibited a microstructural gradient along the anterior-posterior axis of the striatum. The patterns of corticostriatal microstructural covariance are linked to geodesic distance and cell type-specific gene expression profiles, revealing a gradually attenuated relationship along the anterior-posterior axis of the striatum. Linking gene expression profile to corticostriatal microstructural patterns showed that the transcriptional variations in cell type-specific genes are different between the anterior and posterior striatum and suggested that anterior striatum are more enriched in psychiatric disorders. Moreover, at the genetic level, the corticostriatal microarchitecture showed a spatiotemporal trait during neurodevelopment. Finally, we identified the neural circuits from limbic and medial frontal cortex to striatum that contributes to the common neuropsychiatric disorders. Collectively, our findings reveal spatially covarying of transcriptional specializations with microarchitecture of corticostriatal covariance, highlighting the mechanisms underlying that neurodevelopmental corticostriatal circuits may be involved in neuropsychiatric disorders.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"48"},"PeriodicalIF":5.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methods to address functional unblinding of raters in CNS trials.","authors":"Steven D Targum, William P Horan, Vicki G Davis, Alan Breier, Stephen K Brannan","doi":"10.1038/s41398-025-03262-1","DOIUrl":"10.1038/s41398-025-03262-1","url":null,"abstract":"<p><p>Treatment-emergent adverse events (TEAEs) associated with the unique properties of a pharmaceutical product may functionally unblind clinician ratings, obscure true medication effects, and affect confidence about clinical trial results. Central nervous system studies are particularly susceptible to functional unblinding because they rely on relatively subjective symptom assessments. Two different methods were used to examine possible functional unblinding in pooled data from three recent five-week, double-blind, placebo-controlled trials of xanomeline and trospium chloride (formerly known as KarXT) in participants with schizophrenia experiencing acute psychosis. Xanomeline/trospium is an M₁/M₄ muscarinic receptor agonist that may produce cholinergic side effects. First, we compared the scores of remote (site-independent) raters, blinded to TEAEs, who listened to audio recorded, site-based Positive and Negative Syndrome Scale (PANSS) interviews. Second, we conducted a post hoc analysis of participant subgroups with or without reported cholinergic-related TEAEs to ascertain whether cholinergic TEAEs influenced trial outcome. Remote ratings closely replicated 575 available \"paired\" site-based PANSS total scores at baseline and endpoint (intraclass correlation coefficient = 0.88 and 0.93, respectively). Both site-based and remote PANSS scores yielded significant improvement favouring xanomeline/trospium over placebo (both p < 0.0001) and yielded significantly greater treatment response (≥30% improvement from baseline) than placebo (both p < 0.0001). The significant improvement of PANSS scores favouring xanomeline/trospium over placebo was comparable in magnitude for all subgroups regardless of whether participants reported cholinergic-related TEAEs, or any TEAEs at all (all p < 0.001). In sum, the two different methods used to assess functional unblinding in these studies found no impact of cholinergic TEAEs, or any TEAEs, on the trial results. These methods may have utility across all clinical trials.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"47"},"PeriodicalIF":5.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome data based deep learning identified new genes predicting pharmacological treatment response of attention deficit hyperactivity disorder.","authors":"Yilu Zhao, Zhao Fu, Eric J Barnett, Ning Wang, Kangfuxi Zhang, Xuping Gao, Xiangyu Zheng, Junbin Tian, Hui Zhang, XueTong Ding, Shaoxian Li, Shuyu Li, Qingjiu Cao, Suhua Chang, Yufeng Wang, Stephen V Faraone, Li Yang","doi":"10.1038/s41398-025-03250-5","DOIUrl":"10.1038/s41398-025-03250-5","url":null,"abstract":"<p><p>Although the efficacy of pharmacy in the treatment of attention deficit/hyperactivity disorder (ADHD) has been well established, the lack of predictors of treatment response poses great challenges for personalized treatment. The current study employed a comprehensive approach, combining genome-wide association analyses (GWAS) and deep learning (DL) methods, to elucidate the genetic underpinnings of pharmacological treatment response in ADHD. Based on genotype data of medication-naïve patients with ADHD who received pharmacological treatments for 12 weeks, the current study performed GWAS using the percentage changes in ADHD-RS score as phenotype. Then, DL models were constructed to predict percentage changes in symptom scores using genetic variants selected based on four different genome-wide P thresholds (E-02, E-03, E-04, E-05) as inputs. The current GWAS results identified two significant loci (rs10880574, P = 2.39E-09; rs2000900, P = 3.31E-09) which implicated two genes, TMEM117 and MYO5B, that were primarily associated with both brain- and gut-related disorders. The convolutional neural network (CNN) model, using variants with genome-wide P values less than E-02 (5516 SNPs), demonstrated the best performance with mean squared error (MSE) equals 0.012 (Accuracy = 0.83; Sensitivity = 0.90; Specificity = 0.75) in the validation dataset, 0.081 in an independent test dataset (Acc = 0.61, Sensitivity = 0.81; Specificity = 0.26). Notably, the variant that contributed most to the CNN model was NKAIN2, an ADHD-related gene, which is also associated with metabolic processes. To conclude, the integration of GWAS and DL methods revealed new genes contribute to ADHD pharmacological treatment responses, and underscored the interplay between neural systems and metabolic processes, potentially providing critical insights into precision treatment. Furthermore, our CNN model exhibited good performance in an independent dataset, encouraged future studies and implied potential clinical applications.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"46"},"PeriodicalIF":5.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individualized resting-state functional connectivity abnormalities unveil two major depressive disorder subtypes with contrasting abnormal patterns of abnormality.","authors":"Keke Fang, Lianjie Niu, Baohong Wen, Liang Liu, Ya Tian, Huiting Yang, Ying Hou, Shaoqiang Han, Xianfu Sun, Wenzhou Zhang","doi":"10.1038/s41398-025-03268-9","DOIUrl":"10.1038/s41398-025-03268-9","url":null,"abstract":"<p><p>Modern neuroimaging research has recognized that major depressive disorder (MDD) is a connectome disorder, characterized by altered functional connectivity across large-scale brain networks. However, the clinical heterogeneity, likely stemming from diverse neurobiological disturbances, complicates findings from standard group comparison methods. This variability has driven the search for MDD subtypes using objective neuroimaging markers. In this study, we sought to identify potential MDD subtypes from subject-level abnormalities in functional connectivity, leveraging a large multi-site dataset of resting-state MRI from 1276 MDD patients and 1104 matched healthy controls. Subject-level extreme functional connections, determined by comparing against normative ranges derived from healthy controls using tolerance intervals, were used to identify biological subtypes of MDD. We identified a set of extreme functional connections that were predominantly between the visual network and the frontoparietal network, the default mode network and the ventral attention network, with the key regions in the anterior cingulate cortex, bilateral orbitofrontal cortex, and supramarginal gyrus. In MDD patients, these extreme functional connections were linked to age of onset and reward-related processes. Using these features, we identified two subtypes with distinct patterns of functional connectivity abnormalities compared to healthy controls (p < 0.05, Bonferroni correction). When considering all patients together, no significant differences were found. These subtypes significantly enhanced case-control discriminability and showed strong internal discriminability between subtypes. Furthermore, the subtypes were reproducible across varying parameters, study sites, and in untreated patients. Our findings provide new insights into the taxonomy and have potential implications for both diagnosis and treatment of MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"45"},"PeriodicalIF":5.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical trials since 2020 of rapid anti-suicidal ideation effects of ketamine and its enantiomers: a systematic review.","authors":"Sumra Sajid, J John Mann, Michael F Grunebaum","doi":"10.1038/s41398-025-03255-0","DOIUrl":"10.1038/s41398-025-03255-0","url":null,"abstract":"<p><strong>Background: </strong>Suicide is a global public health problem with few empirically supported treatments.</p><p><strong>Methods: </strong>We conducted a systematic review of clinical trials (CT) since 2020 of racemic ketamine or one of its enantiomers' (R/S) potential to reduce suicidal ideation or behavior (SIB). An initial PubMed search on April 15th, 2024 yielded 2483 results. 104 relevant CTs were identified. An additional search using other search engines on March 19th, 2024 yielded 52 sources. After screening, 14 RCTs met the inclusion criteria which required clinically significant SIB among participants, ketamine or one of its enantiomers as an anti-SIB treatment, and SIB as an outcome. We excluded neuroimaging studies, meta-analyses, reviews, and case reports. Open-label studies were also excluded except in the case of R-ketamine where we included 2 open trials due to limited published data for this enantiomer, yielding a total of 16 CTs. We used the Revised Cochrane risk-of-bias tool for the RCTs. CTs reviewed had suicidal ideation (SI) but none had suicidal behavior as an outcome.</p><p><strong>Results: </strong>The studies include ketamine augmentation of other treatments such as electroconvulsive therapy (ECT), various routes of administration - intravenous (IV), intramuscular (IM), and intranasal (IN) - and single versus multiple dose designs. Multiple doses of IV ketamine/S-ketamine produced reductions in SI for periods of several days to weeks, while single doses showed shorter, more variable effects. Multiple and single doses of IN ketamine/S-ketamine and single doses of IV ketamine produced less consistent anti-SI results. IN and IV ketamine/S-ketamine administration appears to be well tolerated. R-ketamine appears to produce fewer side effects, but additional clinical research is needed to clarify its antidepressant and anti-SI effects in humans.</p><p><strong>Conclusion: </strong>This review affirms the time-limited, anti-SI effects of ketamine and the need for personalized treatment. Limitations include study heterogeneity, small samples, and paucity of data for suicidal behavior or R-ketamine.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"44"},"PeriodicalIF":5.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11802767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Randomization and placebo effects in clinical trials of major depressive disorder.","authors":"James A Rogers, Stephen Senn","doi":"10.1038/s41398-025-03263-0","DOIUrl":"10.1038/s41398-025-03263-0","url":null,"abstract":"","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"43"},"PeriodicalIF":5.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}