Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Noribogaine altered intrinsic properties of thalamocortical neurons in a sex-dependent manner","authors":"Sofía Villalba ,&nbsp;Sofia Bosch ,&nbsp;Lucia Di Constanzo ,&nbsp;Bruno González ,&nbsp;Pablo Torterolo ,&nbsp;Ignacio Carrera ,&nbsp;Francisco J. Urbano ,&nbsp;Veronica Bisagno","doi":"10.1016/j.pnpbp.2025.111467","DOIUrl":"10.1016/j.pnpbp.2025.111467","url":null,"abstract":"<div><div>Noribogaine (Noribo) is the primary metabolite from ibogaine, an atypical psychedelic. The main objective of this study was to evaluate the effect of Noribo on thalamic physiology of calcium channels voltage activation and gene expression and the potential involvement of the 5-HT_2A receptor on those effects. Thus, we used male and female, 5-HT_2AR knockout (KO) and wild type (WT) mice, injected with a single Noribo dose (10 or 40 mg/kg; <em>i.p.</em>) and measured thalamic mRNA expression of T-type and P/Q-type calcium channels, as well as HCN2. For CACNA1g (T- type) we found that Noribo 10 increased gene expression of this channel; however, this effect was observed only in WT males and KO females. This result suggests that the effect of Noribo 10 on gene expression is both receptor- and sex-dependent. For CACNA1a (P/Q type), we found that Noribo 10 increased the mRNA expression in both sexes. For HCN2, we found that Noribo 10 decreased the mRNA expression in WT and KO females but only in KO males. We also investigated calcium channel current density by patch-clamp recordings of thalamocortical ventrobasal neurons after bath application of Noribo (50 μM) in slices obtained from WT and KO 5-HT_2AR mice, male and female. We found that bath-applied Noribo blocked T-type calcium current density only in KO females but not in WT. However, in males no blocking effect of Noribo was observed for both genotypes. Also, calcium current density values appeared to be drastically increased in ventrobasal neurons from female mice, another indication of sex-dependent differences.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111467"},"PeriodicalIF":3.9,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “A naturalistic retrospective evaluation of the utility of pharmacogenetic testing based on CYP2D6 and CYP2C19 profiling in antidepressants treatment in a cohort of patients with major depressive disorder” [Progress in Neuropsychopharmacology and Biological Psychiatry (2025) 111292]","authors":"Alessio Squassina ,&nbsp;Pasquale Paribello ,&nbsp;Marco Pinna ,&nbsp;Martina Contu ,&nbsp;Claudia Pisanu ,&nbsp;Donatella Congiu ,&nbsp;Giovanni Severino ,&nbsp;Anna Meloni ,&nbsp;Andrea Carta ,&nbsp;Claudio Conversano ,&nbsp;Francesco Mola ,&nbsp;Maria Del Zompo ,&nbsp;Federico Bernoni d'Aversa ,&nbsp;Alessandra Minelli ,&nbsp;Massimo Gennarelli ,&nbsp;Federica Pinna ,&nbsp;Bernardo Carpiniello ,&nbsp;Mirko Manchia","doi":"10.1016/j.pnpbp.2025.111453","DOIUrl":"10.1016/j.pnpbp.2025.111453","url":null,"abstract":"","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111453"},"PeriodicalIF":3.9,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychostimulants and the cerebellum: Does the cerebellum get involved in the abuse of methamphetamine and cocaine?","authors":"Fatemeh Darvishzadeh-Mahani ,&nbsp;Soodeh Rajabi ,&nbsp;Maryam Alehashem ,&nbsp;Hojjatallah Alaei ,&nbsp;Effat Ramshini","doi":"10.1016/j.pnpbp.2025.111479","DOIUrl":"10.1016/j.pnpbp.2025.111479","url":null,"abstract":"<div><div>Clinical evidence suggests that the cerebellum is one of the brain areas most vulnerable to the effects of psychostimulants. Functional neuroimaging studies support the idea that the cerebellum is involved in the neural circuits affected by these drugs. The cerebellum plays a vital role in the brain's reward mechanisms, working in conjunction with the striatum, ventral tegmental area (VTA), and prefrontal cortex (PFC). The cerebellum plays a crucial role in processing rewards and associated emotions. Research indicates that the cerebellum serves as a central hub for regional disconnection during different mood states. This suggests that mental disorders, including mood disorders and substance use disorders, are linked to the circuitry of the cerebellum. This review provides a comprehensive overview of the brain regions affected by methamphetamine (METH) and cocaine, compiling both clinical and animal evidence regarding the involvement of the cerebellum in the abuse of these drugs. We analyze the effects of METH and cocaine on the cerebellum, detailing the resulting changes in various areas, including imaging, molecular, structural, and functional alterations. By exploring the cerebellum's role in the abuse of METH and cocaine, we can improve our understanding of the underlying mechanisms associated with these substances.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"142 ","pages":"Article 111479"},"PeriodicalIF":3.9,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144979087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The conditioned emotional response evoked by contextual fear is modulated by lateral hypothalamus synaptic activity without the involvement of GABAA receptor activation","authors":"Gabriela L. Bertacchini ,&nbsp;Andreza B. Sonego ,&nbsp;Larissa Fernanda M. Werworn ,&nbsp;Sarah R. Solovi ,&nbsp;Leonardo B.M. Resstel","doi":"10.1016/j.pnpbp.2025.111480","DOIUrl":"10.1016/j.pnpbp.2025.111480","url":null,"abstract":"<div><div>The Lateral Hypothalamic Area (LHA) modulates autonomic responses during defensive reactions. However, the role of the LHA in modulating behavioral and autonomic responses induced by contextual fear conditioning (CFC) remains unclear. To investigate the involvement of the LHA in these responses, we conducted a study using various reversible inhibitors in the LHA.</div><div>Prior to re-exposing the animals to the aversive context, we performed acute, reversible, specific, and non-specific inhibition using lidocaine (100nL), a nonselective synapse inhibitor (CoCl₂, 1 mM/100 nL), or a GABA_A receptor agonist (muscimol, 0.1, 1, and 10 nmol/100 nL) in rats. Unconditioned animals (not exposed to shocks) and conditioned animals (exposed to low- or high-intensity shocks during the conditioning session) exhibited a freezing response and increased autonomic activity (with increased mean arterial pressure and heart rate, while cutaneous temperature decreased) when reintroduced to the chamber. Local inhibition of LHA neurotransmission increased the behavioral response only in the conditioned group subjected to low-intensity shocks. However, unconditioned animals also showed increased autonomic responses. In contrast, inhibition via GABA_A receptor activation did not produce any effects.</div><div>In conclusion, our study provides insights into the complex role of LHA synaptic activity in fear conditioning responses, highlighting its involvement in modulating behavior and autonomic responses based on aversive intensity and indicating that GABA_A receptors are not involved in this process. Additionally, our findings emphasize that the LHA plays a significant role in modulating autonomic activity in both learned and innate threatening scenarios.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111480"},"PeriodicalIF":3.9,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel cannabidiol:tetramethylpyrazine cocrystal (CBD:TMP, ART12.11) improves the efficacy and bioavailability of cannabidiol in reducing stress-induced depressive and anxiety symptoms","authors":"Matthew J. Jones ,&nbsp;Taygun C. Uzuneser ,&nbsp;Saoirse E. O'Sullivan ,&nbsp;Enzo Pérez-Valenzuela ,&nbsp;Mohammed H. Sarikahya ,&nbsp;Andy Yates ,&nbsp;Daniel B. Hardy ,&nbsp;Walter Rushlow ,&nbsp;Steven R. Laviolette","doi":"10.1016/j.pnpbp.2025.111478","DOIUrl":"10.1016/j.pnpbp.2025.111478","url":null,"abstract":"<div><div>Clinical and pre-clinical research has reported promising outcomes for cannabidiol (CBD) in treating mood and anxiety disorder symptoms. However, the pharmacokinetic properties of CBD, such as low and variable bioavailability and low aqueous solubility, limit its therapeutic applications. This study investigated the effects of ART12.11, a novel cannabidiol:tetramethylpyrazine (CBD:TMP) cocrystal, that aims to improve the pharmacotherapeutic potential of CBD by combining it with the co-former tetramethylpyrazine (TMP) to improve CBD's pharmaceutical properties. We used an integrative combination of translational behavioural pharmacology alongside targeted gene and protein expression analyses to characterize the potential anti-depressant and anxiolytic-like effects of ART12.11 in male Sprague Dawley rats, following exposure to chronic stress. In addition, we investigated blood plasma concentrations of CBD and TMP following oral administration of ART12.11 to examine bioavailability. We report that oral administration of ART12.11 reversed stress-induced behavioural deficits and produced significant anti-depressant and anxiolytic-like behavioural effects, which were superior to oral administration of CBD alone, TMP alone, or the co-administration of a non-crystalline mixture of CBD and TMP. Further, we report that ART12.11 resulted in higher blood plasma levels of CBD and its major metabolite, indicating superior bioavailability. Finally, we demonstrate that ART12.11 increased activation of the endocannabinoid and serotonergic systems directly in the prefrontal cortex, ventral hippocampus, and nucleus accumbens. Collectively, our findings indicate that ART12.11 may offer significant advantages over delivering CBD by more traditional approaches in the treatment of mood and anxiety disorders.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111478"},"PeriodicalIF":3.9,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating gene expression, neurochemical signatures, and neurocognitive profiles to decode cortical reorganization in IBS-D","authors":"Qi Zhang ,&nbsp;Meiping He ,&nbsp;Xiaowan Wang ,&nbsp;Jinlong Gao ,&nbsp;Dingbo Guo ,&nbsp;Liyong Yu ,&nbsp;Yue Xu ,&nbsp;Siyi Yu","doi":"10.1016/j.pnpbp.2025.111474","DOIUrl":"10.1016/j.pnpbp.2025.111474","url":null,"abstract":"<div><div>Irritable bowel syndrome with diarrhea (IBS-D) is characterized by persistent gastrointestinal symptoms and marked alterations in brain structure. This study aimed to explore the neurobiological mechanisms that may link these structural changes to the disorder. We investigated hierarchical cortical organization in 31 IBS-D patients and 35 healthy controls (HCs) using morphometric similarity (MS) gradients derived from structural MRI features. Imaging-correspondence analyses were used to decode IBS-D related MS gradient changes with gene expression, neurotransmitter systems, and cognitive functions. Compared to HCs, IBS-D patients exhibited reduced MS gradients in limbic and temporal regions (e.g., entorhinal cortex, superior temporal gyrus) and elevated gradients in fronto-parietal areas (e.g., precuneus, rostral middle frontal cortex). These gradient alterations were spatially correlated with genes enriched for immune response pathways and neurotransmitter systems, including dopamine D2, serotonin 5-HT1a/1b, and GABAa receptors (adjusted R² = 0.38, p_spin = 0.046). Furthermore, gradient shifts overlapped with brain activation patterns linked to emotional regulation (e.g., valence, arousal) and attentional processes (p_FDR &lt; 0.05). Our findings reveal that cortico-limbic gradient reorganization in IBS-D reflects interactions among immune-related genetic pathways and neurotransmitter dysregulation, providing novel targets for interventions addressing brain-gut axis disruptions.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111474"},"PeriodicalIF":3.9,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144895646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Mendelian randomization analysis to identify causal plasma proteins and therapeutic targets for delirium","authors":"Ruijinlin Hao ,&nbsp;Ningwei Su ,&nbsp;Yin Fang ,&nbsp;Chaofang Li ,&nbsp;Yunfan Li ,&nbsp;Hao Cheng ,&nbsp;Zhengnian Ding","doi":"10.1016/j.pnpbp.2025.111477","DOIUrl":"10.1016/j.pnpbp.2025.111477","url":null,"abstract":"<div><h3>Introduction</h3><div>This study aims to identify potentially causal circulating proteins and novel drug targets for delirium using a Mendelian randomization (MR)-based analytical framework and various bioinformatics and genomics methods.</div></div><div><h3>Material and methods</h3><div>Large-scale two-sample MR was employed to estimate the effects of thousands of plasma proteins on delirium. Additional analysis included Bayesian Colocalization, Steiger filtering, protein-altering variant assessment, and mapping of expression quantitative trait loci (eQTL) to protein quantitative trait loci (pQTL). Protein-protein interaction (PPI) networks, pathway enrichment analysis, and evaluation of drug targets were conducted to identify potential therapeutic targets for delirium.</div></div><div><h3>Results</h3><div>Several plasma proteins were identified that show significant causal effects on delirium. Bayesian Colocalization confirmed that these proteins share a common genetic architecture with delirium-associated loci. Steiger filtering analysis validated the direction of causality. Assessment of protein-altering variants and eQTL-pQTL mapping provided further evidence supporting the MR findings. PPI networks and pathway enrichment analysis revealed involvement in key biological processes and pathways related to brain function and neuroinflammation. Several proteins were identified as potential therapeutic targets, offering new avenues for prevention and treatment of delirium.</div></div><div><h3>Conclusions</h3><div>This study identifies several plasma proteins that have a significant causal relationship with delirium, suggesting their potential as biomarkers and therapeutic targets. Our comprehensive analysis using MR, Colocalization, and other bioinformatics approaches strengthens the evidence for these associations. The findings enhance our understanding of the molecular mechanisms underlying delirium and highlight new targets for intervention, which could lead to improved prevention and treatment strategies for this condition.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111477"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144893011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in neurotransmitter-mediated prefrontal circuitry in depression","authors":"Shuyi Li ,&nbsp;Mingzhou Gao ,&nbsp;Zijun Mou ,&nbsp;Haiyan Zhang ,&nbsp;Ying Wang ,&nbsp;Yujiao Zhang","doi":"10.1016/j.pnpbp.2025.111475","DOIUrl":"10.1016/j.pnpbp.2025.111475","url":null,"abstract":"<div><div>Depression, a highly prevalent neuropsychiatric disorder characterised by persistently low mood and anhedonia, poses a severe threat to human health. The prefrontal cortex (PFC), a core brain region governing emotional and cognitive regulation, exhibits dysfunctional neural circuitry that constitutes a key mechanism in the pathogenesis of depression. This article reviews neurotransmitter-mediated PFC-related neural circuits in depression. Dopamine (DA) modulates reward processing and cognitive functions through circuits such as the ventral tegmental area-PFC and PFC-nucleus accumbens. Aberrant receptor function within these circuits leads to imbalanced excitability of PFC pyramidal neurons. Glutamate (Glu), the primary excitatory neurotransmitter, mediates synaptic transmission via <em>N</em>-methyl-<span>d</span>-aspartate/ α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in circuits including the medial PFC (mPFC) and basolateral amygdala. Its dysregulation disrupts the excitation–inhibition balance within the PFC. Serotonin (5-hydroxytryptamine [5-HT]) regulates inhibitory neurons through the mPFC-dorsal raphe nucleus circuit, and reduced 5-HT levels exacerbate emotional disturbances. Gamma-aminobutyric acid (GABA) maintains the stability of PFC circuits via parvalbumin/somatostatin interneurons, and its dysfunction causes excessive excitation. Furthermore, complex interactions exist between neurotransmitters; for instance, DA and Glu synergistically regulate synaptic plasticity, whereas 5-HT and GABA coordinate the inhibitory balance. This review identifies unresolved issues in current research, including unclear mechanisms and heterogeneity. Future studies should explore neurotransmitter interactions and individual differences to provide a theoretical basis for the precise diagnosis and treatment of depression.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111475"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent behavioral and neuronal alterations in the F2 generation of a neurodevelopmental mouse model for schizophrenia","authors":"Yi-Chen Wang ,&nbsp;Yi-Yun Huang ,&nbsp;Er-Deng E ,&nbsp;Chu-Xian Fu ,&nbsp;Jia-Wen Li ,&nbsp;Yu-Wei Mi ,&nbsp;Ning Zhong ,&nbsp;Fei-Ran Yang ,&nbsp;Ting Zhang ,&nbsp;Li-Min Xu ,&nbsp;Xiao-Qin Zhang","doi":"10.1016/j.pnpbp.2025.111476","DOIUrl":"10.1016/j.pnpbp.2025.111476","url":null,"abstract":"<div><div>Schizophrenia is a complex neurodevelopmental disorder influenced by genetic and environmental factors. Using a maternal methylazoxymethanol acetate (MAM) exposure model, we investigated behavioral, neuronal, and glial alterations in the F2 generation to explore the intergenerational effects of prenatal neurodevelopmental disruption. Our study demonstrates that prenatal MAM exposure induces the transgenerational transmission of schizophrenia-like phenotypes in F2 offspring. Both male and female F2 mice exhibited deficits in sensorimotor gating and recognition memory impairments, reflecting core cognitive dysfunctions commonly observed in schizophrenia. Notably, male-specific phenotypes emerged in the form of risk-avoidance deficits, accompanied by significant reductions in NeuN-positive mature neurons and parvalbumin-positive interneurons in the CA1 region of the hippocampus. In contrast, dentate gyrus neurogenesis was impaired in both sexes, while glial cells (microglia and astrocytes) remained unaffected, indicating a neuron-specific vulnerability to intergenerational disruptions. These findings highlight sex-dependent neuronal and behavioral consequences in the offspring of a schizophrenia mouse model, providing insights into intergenerational neurodevelopmental disruptions and their potential contributions to schizophrenia-like phenotypes.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111476"},"PeriodicalIF":3.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual role of Interleukin-18 in linking metabolic and psychiatric symptoms: Insights from machine learning in schizophrenia","authors":"Yali Chai ,&nbsp;Qingrong Xia ,&nbsp;Jian Cheng ,&nbsp;Junwei Yan ,&nbsp;Chao Li ,&nbsp;Xiaoming Kong ,&nbsp;Jiayi Hu ,&nbsp;Jianliang Gao ,&nbsp;Loufeng Zhang ,&nbsp;Peijun Ju ,&nbsp;Cuizhen Zhu","doi":"10.1016/j.pnpbp.2025.111473","DOIUrl":"10.1016/j.pnpbp.2025.111473","url":null,"abstract":"<div><div>Interleukin-18 (IL-18) has been implicated in both metabolic syndrome (MetS) and schizophrenia, but its dual role in their comorbidity remains unclear. This study aimed to explore how IL-18 interacts with metabolic and psychiatric aspects in this context. We recruited 146 participants divided into three groups: MetS (<em>n</em> = 48), non-MetS (<em>n</em> = 54), and healthy controls (<em>n</em> = 44). Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale, while biochemical parameters were measured via an automatic biochemistry analyzer. Levels of 14 cytokines/chemokines, including IL-4, IL-8, IL-10, IL-13, IL-18, and Eotaxin were detected using Meso Scale Discovery (MSD) technology. Linear regression and Gradient Boosting Machine (GBM) models revealed that IL-18 significantly impacted metabolic indices (e.g., triglycerides, waist circumference, BMI) and psychiatric symptoms (e.g., psychopathology score, aggressiveness score, PANSS total score) in the MetS group. Analysis using Partial Dependence Plots (PDP) and Accumulated Local Effects (ALE) plots revealed that IL-18 had complex, non-linear interactions with metabolic markers and clinical symptoms. To further elucidate the comprehensive effects of IL-18 on metabolism and symptoms, we integrated these markers into two overarching domains: metabolic and symptomatic. Extreme Gradient Boosting (XGBoost) regression models and SHapley Additive exPlanations (SHAP) values were then employed to quantify the influence of IL-18 on these domains. Results indicated that IL-18's impact on clinical symptoms was more pronounced at lower levels, diminishing as its concentration increased, while its metabolic impact was more significant at higher levels. This study highlights IL-18's dual role as an inflammatory bridge between metabolic dysregulation and psychopathology in comorbidity and underscores the need for further investigation into the underlying mechanisms driving these non-linear interactions.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"141 ","pages":"Article 111473"},"PeriodicalIF":3.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}