Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献

{"title":"Tactile stimulation modulates glucocorticoid receptor and activates the BDNF Cascade in the substantia nigra of haloperidol-treated rats: A sequential investigation into nigrostriatal plasticity.","authors":"J L O Rosa, P Brivio, D R Rossato, M B Fontoura, L E M Souza, C T D Antoniazzi, F Fumagalli, F Calabrese, M E Burger","doi":"10.1016/j.pnpbp.2025.111525","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111525","url":null,"abstract":"<p><p>Tactile stimulation (TS) is a sensory intervention successfully applied to premature neonates and extensively studied in various animal models of neuropsychiatric conditions, as well as in other contexts. Haloperidol is a first-generation antipsychotic, and its use leads to serious adverse effects such as the extrapyramidal syndrome, which promotes movement disorders including Parkinsonism, akathisia and tardive dyskinesia. We recently demonstrated that TS can reduce haloperidol-induced movement disorders, promoting changes in the dopaminergic and glutamatergic systems. Furthermore, studies have shown that TS can prevent the development of depressive-like behaviors and the negative effects of stress, and it can also reduce anxiety-like behaviors by enhancing neurogenesis and neuroplasticity. In this sense, we aimed to explore whether TS can modulate these mechanisms in haloperidol-exposed animals. Our findings showed that TS exposure restored Grβ mRNA levels, activating the glucocorticoid-responsive element Rack1, which in turn promotes Bdnf transcription. This effect was observed through the increased levels of the Bdnf long 3'UTR isoform and mBDNF, along with the activation of its signaling cascade, as indicated by increased levels of AKT and S6. Based on these outcomes, we can infer that, even when applied to adult animals, TS is capable of exerting favorable molecular neuroadaptations in the Substantia nigra, as evidenced by the promotion of neurogenesis and the enhancement of neuroplasticity. This study also provides, for the first time, evidence of the molecular effects of TS on the Substantia nigra of rats previously exposed to haloperidol, with changes reflected in glucocorticoid isoforms and the BDNF signaling cascade.</p>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111525"},"PeriodicalIF":3.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304270","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-specific amygdala connectivity alterations in medication-naïve major depressive disorder: A static and dynamic analysis.","authors":"Chunyu Yang, Yuanyuan Li, Yuting Wang, Hongli Yang, Yanxin Ling, Li Wang, Jing Su, Yongsheng Ao, Yan Cheng, Jiaojian Wang, Lihua Qiu","doi":"10.1016/j.pnpbp.2025.111523","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111523","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder (MDD) represents a leading contributor to the global disease burden, characterized by pronounced sex differences in prevalence and symptom expression. The amygdala, as a critical node within the brain's affective circuitry, has been implicated in MDD pathophysiology. However, the neurobiological mechanisms underlying sex-specific vulnerability and clinical heterogeneity in MDD remain incompletely understood. This study aimed to investigate sex-stratified alterations in amygdala functional connectivity (FC) using both static and dynamic connectivity frameworks in medication-naïve MDD patients.</p><p><strong>Methods: </strong>We employed seed-based FC analyses anchored in the amygdala to examine static FC (sFC) and dynamic FC (dFC) in 61 age- and sex-matched MDD patients and 61 healthy controls (HCs).</p><p><strong>Results: </strong>Significant sex-by-diagnosis interactions were identified in amygdala-striatal circuitry connectivity. Female MDD patients exhibited aberrant dFC patterns involving the visual network and sensorimotor network, characterized by heightened dynamic coupling compared to male patients. Conversely, reduced dFC was observed between the right amygdala and right superior cerebellum in female MDD patients relative to male counterparts. Notably, static and dynamic FC demonstrated divergent directional effects within the same sex, suggesting dissociable neurobiological mechanisms across temporal scales.</p><p><strong>Limitation: </strong>The cross-sectional design and relatively small sample size may limit the generalizability of findings.</p><p><strong>Conclusions: </strong>These findings elucidate sex-differentiated amygdala connectivity phenotypes in MDD, highlighting sexually dimorphic neurocircuitry mechanisms that may underlie differential disease manifestation. These data advance our understanding of MDD's neurobiological substrates and may inform the development of sex-specific diagnostic criteria and personalized treatment strategies.</p>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111523"},"PeriodicalIF":3.9,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294397","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":"Imbalance of habit-based versus goal-directed learning in internet gaming disorder: evidence from fMRI and behavioral performance.","authors":"Hui Zheng, Xuefeng Ma, Min Wang, Ziliang Wang, Chunlei Lu, Guang-Heng Dong","doi":"10.1016/j.pnpbp.2025.111524","DOIUrl":"10.1016/j.pnpbp.2025.111524","url":null,"abstract":"<p><strong>Background: </strong>The balance between habit control action and goal-directed action of the instrumental learning processes contributes to the development and maintenance of addictive behavior. However, the neural mechanisms underlying this imbalance in internet gaming disorder (IGD) remain unexplored.</p><p><strong>Methods: </strong>Functional MRI data were collected from 26 IGD and 28 matched recreational game users (RGU) during a discriminative instrumental learning task. Behavioral performance and task-related brain activation was compared between the IGD and RGU. Correlations between addiction severity (IAT scores) and neural/behavioral measures were analyzed.</p><p><strong>Results: </strong>Compared with RGU, the IGD group exhibited poorer behavioral performance, characterized by hyperactivation in the right inferior frontal gyrus, bilateral precuneus, bilateral lingual gyrus, and left precentral gyrus, alongside hypoactivation in the left inferior frontal gyrus. Notably, addictive severity scores negatively correlated with accuracy in the outcome devaluation stage, indicating a reliance on habitual control.</p><p><strong>Discussion: </strong>Our findings suggest that IGD is associated with a shift from goal-directed to habit-based control, marked by dysfunctional engagement of prefrontal-striatal circuits. This imbalance may underlie the compulsive gaming behaviors observed in IGD, offering novel insights into its neurocognitive mechanisms.</p>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111524"},"PeriodicalIF":3.9,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145294357","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":"Differential effects of psilocybin and lisuride on serotonin and dopamine neuronal activity and behavior.","authors":"Brandon Richardson, Antonio Inserra, Michael Pileggi, Thomas Prud'Homme, Vitor Bruno, Derek Wan-Yan-Chan, Ilia Shareghi-Ghahreman, Sofia Nasini, Tadhg Strand, Marco Leyton, Nahum Sonenberg, Danilo De Gregorio, Jeffrey Sprouse, Francis R Bambico, Gabriella Gobbi","doi":"10.1016/j.pnpbp.2025.111522","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111522","url":null,"abstract":"<p><p>Psilocybin and lisuride are 5-HT_2A receptor agonists, but only psilocybin elicits the head twitch response (HTR) in rodents, a behavior commonly used as a proxy for hallucinogenic activity. This study aimed to compare their effects on serotonin (5-HT) and dopamine (DA) neuronal activity, as well as related behavioral outcomes, to elucidate the mechanisms underlying their divergent effects. Adult male C57BL/6 N mice were administered intraperitoneal injections of psilocybin (0.3-3 mg/kg), lisuride (0.1-0.5 mg/kg), or vehicle. In vivo electrophysiological recordings were performed in the dorsal raphe nucleus (DRN) and substantia nigra (SN) to monitor 5-HT and DA neuronal firing. MDL 100907 (0.2 mg/kg) pretreatment was used to determine 5-HT_2A receptor specificity. Behavioral assessments included HTR testing 10 min post-injection, followed by either the forced swim test (FST), open field test (OFT), or elevated plus maze (EPM) at 20 min post-injection. Psilocybin-induced inhibition, but not lisuride-induced inhibition, of 5-HT neuron firing was blocked by MDL 100907. Both drugs reduced DA neuron firing, however, lisuride's effect was more sensitive to 5-HT_2A receptor antagonism. Psilocybin elicited HTR, while lisuride did not. In the FST, only high-dose lisuride reduced immobility time. Both drugs reduced locomotor activity in the OFT and EPM. Principal Component Analysis (PCA) sufficiently separated the effects of each drug from each other, indicating distinct effect profiles. Although both drugs target 5-HT_2A receptors, they engage distinct neurobiological pathways. Psilocybin produces psychedelic-like, 5-HT-dominant effects, whereas lisuride displays DA-linked improvements in coping behavior, informing future development of serotonergic therapeutics.</p>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111522"},"PeriodicalIF":3.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281804","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 possible effect of fentanyl on PTSD.","authors":"Yehudit O Weiss Schonberg, Leehe Peled-Avron","doi":"10.1016/j.pnpbp.2025.111519","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111519","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is a severe mental health disorder that appears as a result of trauma exposure and adversely affects the daily life and well-being of those who suffer from it. Major risk factors for PTSD include serving as a combat soldier and having traumatic and painful injuries. This review aims to investigate the possible beneficial effects of fentanyl on PTSD, and the possible theoretical mechanisms at the base of these effects. Fentanyl is a powerful analgesic from the opioid family that is often administered in cases of painful injuries, both as a prehospital battlefield treatment and at the hospital. Morphine, another opioid used for analgesia in similar situations, was shown to help both with the prevention and treatment of PTSD. Only a few studies examine the direct influence of fentanyl on PTSD, but there is evidence that indirectly suggests that fentanyl can treat or prevent PTSD via three mediating factors. In this review we suggest three possible hypotheses. In one possible route, the influence of fentanyl on PTSD is mediated by pain relief. Fentanyl was found to effectively reduce pain, and a positive correlation between pain level and PTSD severity was also found. The second route suggests that fentanyl's influence on PTSD is mediated by the activity of the vagus nerve. There is evidence that fentanyl administration results in vagal activity and that the activation of the vagus nerve reduces PTSD levels. A third possible route may be through fentanyl's activation of opioid receptors in limbic region which were found to have protective effects against PTSD. Future research of fentanyl's role in PTSD prevention and treatment is essential, and should account for pre-existing mental health struggles, TBI, delirium, and injury severity.</p>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111519"},"PeriodicalIF":3.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276605","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 effect of sertraline and voluntary exercise during pregnancy on litter characteristics and postpartum affective behaviour in rat dams.","authors":"Noor S Jarbou, Olivia Mairinger, Elise Kulen, Lucas Mushahwar, Samara Walpole, Jasmine Matthews, Simon Maksour, Katrina Weston-Green, Mirella Dottori, Kelly A Newell","doi":"10.1016/j.pnpbp.2025.111520","DOIUrl":"https://doi.org/10.1016/j.pnpbp.2025.111520","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Sertraline is the frontline pharmacotherapy for the treatment of depression and anxiety during pregnancy. However, there is little evidence regarding the effects of sertraline on maternal behaviour or the maternal brain. Furthermore, the efficacy of non-pharmacological approaches to treatment in pregnancy, such as exercise, are unclear. Therefore, the aim of this study was to examine the effects of sertraline and exercise during pregnancy on maternal postpartum depressive-like, anxiety-like and associated behaviours, as well as litter characteristics, in a rat model of depression. We also investigated the effects of these treatments on the maternal brain, focusing initially on DNA methylation and glutamatergic markers, which have been implicated in depression.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Method: &lt;/strong&gt;Twenty-four female Wistar-Kyoto (WKY; strain that models depression and anxiety) rats were divided into three groups: 1. WKY-Sertraline; 2. WKY-Exercise, 3. WKY-Vehicle; Six female Wistar (WIS) rats were included as controls. Rats were treated with sertraline (10 mg/kg) or vehicle (33 % propylene glycol) twice/day, from gestational day (GD) 1 to postpartum day 14. The WKY-Exercise group were provided access to a running wheel during pregnancy for 3 h/day from GD1-18. Dam and litter characteristics, as well as pup ultrasonic vocalisations (USVs), were measured. Dams underwent behavioural testing at 5-weeks postpartum to assess depressive-, anxiety- and cognitive-like behaviours. Gene expression of DNA methylation markers (Dnmt1, Dnmt3a) and glutamate receptors (Grin1, Grin2a, Grin2b) were measured in the prefrontal cortex (PFC), using RT-qPCR.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Result: &lt;/strong&gt;The WKY-Sertraline group gained 39 % less weight in their first pregnancy week compared to all other groups (p &lt; 0.05) and produced smaller litters compared to WIS controls (-43 %; p = 0.003) and WKY-Exercise (-38 %; p = 0.012); WKY-Sertraline pups had slightly smaller brain weights compared to WKY-Vehicle (p = 0.031). WKY-Vehicle pups showed reduced number of USV calls, call amplitude and call duration compared to WIS control (p &lt; 0.001). The WKY-Exercise pups produced increased number of USVs, with increased call amplitude of USVs, at postnatal day (PN)7 compared to WKY-Vehicle (p &lt; 0.01). Maternal sertraline treatment did not significantly affect dam behavioural measures, or maternal cortical gene expression. The WKY-Exercise group however showed reduced anxiety-like behaviours, spending more time in the open arms (620 %; p = 0.027) and less time in the closed arms (-22 %; p = 0.047) of the elevated plus maze (EPM) compared to WKY-Vehicle, and more time in the centre of the open field test (OFT) compared to WKY-Vehicle (132 %; p = 0.057). Furthermore, WKY-Exercise dams showed a 64 % increase in Dnmt3a mRNA levels in the PFC compared to WKY-Vehicle (p = 0.019), effectively reversing the 44 % reduction observed in WKY-Veh relative to WIS controls (p = 0.009","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":" ","pages":"111520"},"PeriodicalIF":3.9,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276648","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":"Neurogliovascular unit adaptations following chronic distress predict motivational deficits in mice","authors":"Lidia Cabeza ,&nbsp;Damien Mor ,&nbsp;Bahrie Ramadan ,&nbsp;Guillaume Benhora-Chabeaux ,&nbsp;Christophe Houdayer ,&nbsp;Emmanuel Haffen ,&nbsp;Yvan Peterschmitt ,&nbsp;Adeline Etievant ,&nbsp;Fanchon Bourasset","doi":"10.1016/j.pnpbp.2025.111510","DOIUrl":"10.1016/j.pnpbp.2025.111510","url":null,"abstract":"<div><div>The neurogliovascular unit (NGVU) reflects the complex interplay between neural tissue and blood flow. Dysfunction in this NGVU system is involved in neuropsychiatric disorders, however, whether the alterations are a cause or consequence of these conditions remains unclear. This study investigates the role of NGVU adaptations in motivational deficits associated with depressive episodes, focusing on blood vessel structural changes and blood-brain barrier (BBB) permeability. We used brain samples from adult male C57BL/6jRj mice that were chronically treated with corticosterone (CORT), and which presented severe motivational deficits in an operant progressive ratio task, along with altered neural activation in brain regions involved in motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area), as assessed by FosB expression. NGVU modifications were first evaluated through immunofluorescence staining for microglia (IBA-1), endothelial tight junctions (ZO-1), and astrocytes (GFAP). BBB permeability was assessed using intravenous perfusion of fluorescent 40 kDa Dextran. Principal component analysis revealed that NGVU alterations in the ventral tegmental area and basolateral amygdala predicted motivational deficits in CORT-treated mice. Specifically, ZO-1 expression was downregulated, and Dextran extravasation was increased in these regions. These findings suggest that NGVU adaptations induced by chronic CORT exposure impact BBB integrity and are integral to understanding behavioural performance. In conclusion, NGVU modifications may play a key role in the cognitive and behavioural dysfunction seen in neuropsychiatric disorders, highlighting their relevance in the biological substrate of these conditions.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"142 ","pages":"Article 111510"},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180064","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":"Oral guanfacine treatment ameliorates the ADHD-like symptoms caused by developmental manganese exposure","authors":"Ellie Fisher ,&nbsp;Stephane A. Beaudin ,&nbsp;Barbara J. Strupp ,&nbsp;Donald R. Smith","doi":"10.1016/j.pnpbp.2025.111517","DOIUrl":"10.1016/j.pnpbp.2025.111517","url":null,"abstract":"<div><div>Epidemiological studies have linked developmental manganese (Mn) exposure to increased risk of ADHD and related symptoms in children and adolescents. Rodent model studies have 1) confirmed causality by demonstrating that developmental Mn exposure can cause lasting ADHD-like symptoms, 2) revealed that these symptoms (in Mn-exposed animals) are accompanied by a hypofunctioning catecholaminergic system in fronto-cortical-striatal brain areas, and 3) demonstrated that methylphenidate is efficacious in ameliorating these ADHD-like symptoms in Mn-exposed animals. However, stimulant medications such as methylphenidate do not lessen symptoms in 25–30 % of children and adolescents diagnosed with ADHD, indicating the need for alternative ADHD medications. Guanfacine, a specific noradrenergic α_2A receptor agonist, has proven to be an effective non-stimulant ADHD medication, although it is unknown whether this drug is effective in treating the ADHD-like symptoms produced by developmental Mn exposure. The present study was designed to test this hypothesis. Additionally, due to the pharmacological specificity of guanfacine, its use may provide mechanistic insight into the role of noradrenergic dysfunction as a contributor to the Mn-induced impairments. Male Long-Evans neonatal rats were orally dosed with vehicle or Mn (50 mg Mn/kg/d) from postnatal day 1–21, and orally treated with guanfacine (0, 0.1, or 0.3 mg/kg/d) during behavioral testing as adults. The results revealed that developmental Mn exposure produced lasting impairments in impulse control, attention, and sensorimotor function, and that oral guanfacine was efficacious in ameliorating the Mn-induced impairments in all three functional domains, although the treatment duration needed for efficacy varied by functional domain. In addition, in control (unexposed) animals, there was little or no effect of guanfacine on any functional domain. There was also little effect of the drug in the Mn-exposed animals under trial conditions where Mn deficits did not emerge. These findings 1) demonstrate the efficacy of oral guanfacine to ameliorate the lasting ADHD-like symptoms caused by developmental Mn exposure, and 2) provide additional support for the hypothesis that hypofunctioning of the noradrenergic system contributes to these lasting Mn deficits. Collectively, these findings suggest that individuals with environmentally-induced ADHD, such as that induced by developmental Mn exposure, may benefit from oral guanfacine treatment.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"142 ","pages":"Article 111517"},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245277","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":"Polygenic predisposition to transdiagnostic symptom dimensions and treatment outcomes across psychiatric disorders","authors":"Paolo Abondio ,&nbsp;Giuseppe Fanelli ,&nbsp;Valentina Baldini ,&nbsp;Maria Giulia Bacalini ,&nbsp;Siegfried Kasper ,&nbsp;Joseph Zohar ,&nbsp;Daniel Souery ,&nbsp;Stuart Montgomery ,&nbsp;Diego Albani ,&nbsp;Gianluigi Forloni ,&nbsp;Panagiotis Ferentinos ,&nbsp;Dan Rujescu ,&nbsp;Julien Mendlewicz ,&nbsp;Alessandro Serretti ,&nbsp;Alessio Maria Monteleone ,&nbsp;Luigi Grassi ,&nbsp;MNESYS - Mood and Psychosis Sub-ProjecEt (Spoke 5) ,&nbsp;Anna Rita Atti ,&nbsp;Marco Menchetti ,&nbsp;Chiara Fabbri ,&nbsp;Diana De Ronchi","doi":"10.1016/j.pnpbp.2025.111512","DOIUrl":"10.1016/j.pnpbp.2025.111512","url":null,"abstract":"<div><h3>Background</h3><div>Mood and psychotic disorders, including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ), show overlapping symptoms that challenge diagnostic boundaries and may inform personalised treatments. We examined the contribution of genetic liability to transdiagnostic symptom dimensions in treatment outcomes across disorders using polygenic scores (PGSs).</div></div><div><h3>Methods</h3><div>We analysed two MDD cohorts (total <em>N</em> = 2548), one BD cohort (<em>N</em> = 755), and one SCZ cohort (<em>N</em> = 449). Outcomes included treatment resistance, symptomatic remission, and change in functioning defined using cohort-specific data. PGSs for anhedonia, anxiety, sociability, resilience, cognitive and sleep-related traits were computed using SBayesRC. Regressions adjusted for potential confounders were run in each cohort and results meta-analysed with random-effects models; heterogeneity was assessed with leave-one-out and influence diagnostics, and meta-regressions. Multiple testing was controlled using a Bonferroni correction adjusted for the effective number of independent tests (α_adj = 0.0034).</div></div><div><h3>Results</h3><div>In meta-analyses, no result survived multiple testing correction. The strongest signal was for the Trail Making Test Part B PGS, indexing worse executive function/processing speed, and non-remission (OR = 1.13, <em>p</em> = 0.012; I² = 13 %); modelling diagnosis (mood disorders vs SCZ) reduced heterogeneity to I² = 0 %, and leave-one-out excluding SCZ reached statistical significance (OR = 1.17, <em>p</em> = 0.001). Verbal-numerical reasoning PGS, indexing predisposition to higher fluid intelligence, was nominally associated with improved functioning (β = −0.06, <em>p</em> = 0.016), confirmed in leave-one-out excluding BD (β = −0.07, <em>p</em> = 0.0095).</div></div><div><h3>Conclusion</h3><div>PGSs for cognitive traits showed trait- and diagnosis-specific associations with treatment outcomes. Cross-diagnostic analyses may identify shared genetic influences, but variability in symptom expression across disorders may introduce heterogeneity and reduce the detectability of such effects.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"142 ","pages":"Article 111512"},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193838","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":"Impaired deviance detection as the core psychopathological mechanism of schizophrenia","authors":"Yi Fan Zhang ,&nbsp;Michiel Spape ,&nbsp;Yu-Tao Xiang ,&nbsp;Kuzma Strelnikov","doi":"10.1016/j.pnpbp.2025.111516","DOIUrl":"10.1016/j.pnpbp.2025.111516","url":null,"abstract":"<div><div>Understanding the core psychopathological mechanism of schizophrenia is crucial for its diagnosis and treatment. In this article, we update the evidence for our previous proposal that the core of neurocognitive dysfunctions in schizophrenia is the impairment of deviance detection. We discuss the dysfunction of the <em>N</em>-methyl-<span>d</span>-aspartate (NMDA) receptors in schizophrenia, which resembles that induced by ketamine and leads to a reduced mismatch negativity in electroencephalography (EEG), and we demonstrate that the genetic findings and structural changes in the brain associated with schizophrenia correspond to impaired deviance detection as the core cognitive impairment. In a broader psychopathological perspective, this impairment disrupts the interaction between predictive and evidence-based mechanisms of speech processing in the brain, which may help elucidate the emergence of core symptoms such as delusions and hallucinations. Furthermore, we discuss how disruptions in deviance detection contribute to negative symptoms and significantly hinder everyday functioning and autonomy in individuals with schizophrenia.</div><div>Integration of numerous findings into this model provides compelling evidence that impaired deviance detection is a prominent contributor to the manifestation of symptoms and the pathological progression of this psychiatric condition. We suggest that targeting the core cognitive deficiency, that of deviance detection may enhance psychological and pharmacological approaches to diagnose and rehabilitate schizophrenia.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"142 ","pages":"Article 111516"},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240263","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}