Neuropsychopharmacology最新文献

{"title":"NAc-DBS selectively enhances memory updating without effect on retrieval","authors":"Andrés Pérez-Segura, Jorge Medina, Antonio Cerdán Cerdá, Cristina Sánchez-Ferri, Daniel Torres, Claudio R. Mirasso, Bryan Strange, Víctor M. Eguíluz, Lucas Lacasa, Santiago Canals","doi":"10.1038/s41386-025-02132-0","DOIUrl":"10.1038/s41386-025-02132-0","url":null,"abstract":"Deep brain stimulation (DBS) has emerged as a widely used therapeutic option when pharmacological treatments prove ineffective or refractory for psychiatric patients. The nucleus accumbens (NAc) represents a frequently targeted site in DBS interventions due to its demonstrated safety profile and therapeutic efficacy in obsessive-compulsive disorder, major depression, and anorexia nervosa. However, limited mechanistic understanding hampers its broader clinical applicability. This study sought to delineate the distinct behavioural dimensions modulated by NAc-DBS, its impact on distinct facets of memory, and to elucidate the underlying brain-network mechanism of action. We developed a novel spatial navigation task for rats and employed a high-dimensional behavioural analysis complemented by fMRI to dissect the cognitive, behavioural and neurobiological effects of NAc-DBS. Active NAc-DBS in male rats produced a selective enhancement of long-term memory encoding without affecting memory recall or working memory. We found a small but statistically significant rewarding effect of NAc-DBS, with no detectable impact on motor or stress-related behaviours. Sustained neuronal activation in the NAc, septum, entorhinal and insular cortex demonstrated no desensitisation to chronic NAc-DBS, which triggered a functional reorganisation among dopaminergic-related structures. These findings suggest that NAc-DBS induces a functional reorganisation in the mesocorticolimbic system, potentially mimicking a dopaminergic novelty signal to enhance memory updating. This provides a mechanistic basis for the therapeutic use of NAc-DBS, particularly in improving cognitive flexibility in psychiatric disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1420-1429"},"PeriodicalIF":6.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02132-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164607","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":"Cortical myelin mapping in antipsychotic medication-naïve, first-episode psychosis patients","authors":"Victoria L. King, Gerhard Hellemann, Adrienne C. Lahti, Matthew Defenderfer, Jill R. Glausier, Hui Zhang, Nina V. Kraguljac","doi":"10.1038/s41386-025-02137-9","DOIUrl":"10.1038/s41386-025-02137-9","url":null,"abstract":"While white matter myelin primarily functions to accelerate conduction velocity and has been extensively studied in schizophrenia-spectrum disorders (SSD), less is known about the role of gray matter myelin in SSD. Cortical myelination occurs mostly on the proximal axons of parvalbumin positive (PV+) interneurons, where it assists in trophic support and experience-dependent plasticity. Given the role of PV+ interneuron dysfunction in SSD, it is critical to advance our understanding of cortical myelin pathology in this context. Here, we quantified myelin maps using the T1w/T2w ratio in a large group of antipsychotic medication-naïve, first-episode psychosis patients. We compared myelin content between patients (N = 91) and controls (N = 107) using a MANCOVA and calculated zero-order correlations with the discriminant function for each region, then used a machine learning approach to identify the most parsimonious constellation of cortical regions driving group differences using a stepwise algorithm. Group membership was significantly associated with T1w/T2w ratio (Wilks Lambda = 0.09, p < 0.01), where patients had higher myelin values compared to healthy controls. We identified a subset of 16 regions, primarily located in association cortices, that were sufficient to explain group differences. Here, we report an increase in the cortical T1w/T2w ratio in association cortices in first-episode psychosis. We suggest that faulty myelin compaction during this critical developmental period could contribute to PV+ interneuron pathology and cortical microcircuit disruptions resulting in the clinical phenotype. With additional empirical support from future studies, novel treatment strategies targeting cortical myelin could have potential to mitigate circuit dysfunction in the illness.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1439-1445"},"PeriodicalIF":6.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02137-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132041","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":"The Tailtag: A multi-mouse tracking system to measure social dynamics in complex environments","authors":"Vincent Coulombe, Arturo Marroquin Rivera, Sadegh Monfared, David-Alexandre Roussel, Quentin Leboulleux, Modesto R. Peralta III, Benoit Gosselin, Benoit Labonté","doi":"10.1038/s41386-025-02126-y","DOIUrl":"10.1038/s41386-025-02126-y","url":null,"abstract":"Despite recent advances, tracking individual movements safely and reliably over extended periods, particularly within complex social groups, remains a challenge. Traditional methods like color coding, tagging, and RFID tracking, while effective, have notable practical limitations. State-of-the-art neural network-based trackers often struggle to maintain individual identities in large groups for more than a few seconds. Fiducial tags such as ArUco codes present a potential solution to enable accurate tracking and identity management. However, their application to large groups of socially interacting mice in complex, enriched environments remain an open challenge. Here, we present the Tailtag system, a novel approach designed to address this challenge. The Tailtag is a non-invasive, safe, and ergonomic tail ring embedded with an ArUco marker allowing to track individual mice in colonies of up to 20 individuals in complex environments for at least seven days without performance degradation or behavioral alteration. We provide a comprehensive parameter optimization guide and practical recommendations for marker selection, for reproducibility across diverse experimental setups. Using data collected from Tailtag-equipped mice, we revealed the formation and evolution of social groups within the colony. Our analysis identified social hub regions within the vivarium where social contacts occur at different frequencies throughout one week of recordings. We quantified interactions and avoidance patterns between specific pairs of mice within the most active social hubs. Overall, our findings indicate that while the zone preferences and peer associations among the mice change over time, certain groups and pairwise interactions consistently form within the social colony.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1336-1345"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02126-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129902","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":"DLPFC: The Decade circLe CCNP Family Cohort","authors":"Zhe Zhang, Ning Yang","doi":"10.1038/s41386-025-02131-1","DOIUrl":"10.1038/s41386-025-02131-1","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1617-1619"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress-related genetic factors modify the effect of socioeconomic status on cardiovascular risk","authors":"Krystel Abi Karam, Shady Abohashem, Hui Chong Lau, Giovanni Civieri, Wesam Aldosoky, Maria Khalil, Gagandeep Singh Arora, Robert Rollings, Alula Assefa, Taha Z. Ahmad, Jamie W. Bellinge, Azar Radfar, Karmel Choi, Jordan W. Smoller, Antonia V. Seligowski, Ahmed Tawakol, Michael T. Osborne","doi":"10.1038/s41386-025-02130-2","DOIUrl":"10.1038/s41386-025-02130-2","url":null,"abstract":"Lower socioeconomic status (SES) and higher neuroticism polygenic risk score (NEU-PGS) associate with cardiovascular disease (CVD). Chronic stress increases CVD risk via activation of neural, autonomic, and immune pathways. We evaluated whether 1) higher NEU-PGS accentuates the association between lower SES and major adverse cardiovascular events (MACE); and 2) higher stress-associated neural activity and C-reactive protein and lower heart rate variability contribute to the SES-MACE link among those with higher NEU-PGS. NEU-PGS (from those with European ancestry) and SES data were derived from individuals in the Mass General Brigham Biobank. SES was assessed as median household income (N = 18,093) and area deprivation index (ADI, N = 15,276). Lower household income was defined as the lowest tertile and higher ADI as the highest. NEU-PGS was stratified about the population median. MACE, stress-associated neural activity, heart rate variability, and C-reactive protein were assessed from clinical data. Among individuals with higher (but not lower) NEU-PGS, lower household income associated with MACE (N = 6,574; OR: 1.22, p = 0.005), stress-associated neural activity (N = 480; standardized β: 0.14, p = 0.003), and heart rate variability (1,361; −0.05, p = 0.041). Higher ADI associated with MACE (5,441; 1.24, p = 0.008) and heart rate variability (1,127; −0.09, p = 0.001) among those with higher (but not lower) NEU-PGS. Lower SES associated with higher C-reactive protein across NEU-PGS groups. The mediating effect of stress-associated neural activity, heart rate variability and C-reactive protein in the SES-MACE relationship was moderated by higher NEU-PGS. Individuals with higher NEU-PGS experience greater CVD risk related to lower SES via alterations in neural, autonomic, and immune mechanisms.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1327-1335"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The efficacy of elevating anandamide via inhibition of fatty acid amide hydrolase (FAAH) combined with internet-delivered cognitive behavioral therapy in the treatment of post-traumatic stress disorder: a randomized, placebo-controlled clinical trial","authors":"Leah M. Mayo, Emelie Gauffin, Gavin N. Petrie, Ryann Tansey, Raegan Mazurka, Connor J. Haggarty, Madeleine R. Jones, Hilda Engelbrektsson, Victoria Aminoff, Anisja Hühne-Landgraf, Mark E. Schmidt, Darrel J. Pemberton, Cecilia Fredlund, Lars Östman, Hanna Karlsson, Andreas Löfberg, Michal Pietrzak, Gerhard Andersson, Andrea Johansson Capusan, Matthew N. Hill, Markus Heilig","doi":"10.1038/s41386-025-02128-w","DOIUrl":"10.1038/s41386-025-02128-w","url":null,"abstract":"Post-traumatic stress disorder (PTSD) is a severe mental health disorder with limited treatment options. Gold standard treatment includes cognitive behavioral therapies (CBT) that incorporate exposure to traumatic memories to facilitate extinction. CBT can be effective in PTSD, but effects are incomplete and symptoms are prone to spontaneous return. Pharmacologically facilitating fear extinction could potentiate the effects of exposure-based therapy. Here, we explored whether targeting the endocannabinoid (eCB) system, a neuromodulatory system critically involved in fear extinction, would promote the efficacy of exposure-based CBT. Specifically, we tested the effects of elevating the eCB ligand anandamide (AEA) via inhibition of its main degradative enzyme, fatty acid amide hydrolase (FAAH). In this double-blind, placebo-controlled study, patients with PTSD (N = 100; 85 women) were randomized to the FAAH inhibitor (FAAHi) JNJ-42165279 (25 mg b.i.d.) or placebo for 12 weeks. In weeks 5–12, all participants completed an internet-delivered CBT that included exposure-based modules. The primary outcome was clinician-assessed PTSD symptom severity (CAPS-5). Secondary outcomes included self-reported symptoms of PTSD, depression, anxiety, and sleep quality. Blood samples were taken to measure levels of drug and eCBs. Overall, PTSD symptoms improved over time. While FAAHi increased AEA levels, there was no effect of FAAHi on PTSD symptoms or any secondary measure. FAAHi combined with internet-delivered CBT did not improve PTSD symptoms to a greater extent than internet-delivered CBT alone. Thus, FAAH inhibition does not appear to be a suitable adjunct treatment for enhancing CBT in PTSD. This study was registered as Eudra-CT 2020-001965-36.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1564-1572"},"PeriodicalIF":6.6,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02128-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144096766","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":"Effects of NMDA receptor antagonists on working memory and gamma oscillations, and the mediating role of the GluN2D subunit.","authors":"Chitra Vinnakota, Matthew R Hudson, Kazutaka Ikeda, Soichiro Ide, Masayoshi Mishina, Suresh Sundram, Nigel C Jones, Rachel Anne Hill","doi":"10.1038/s41386-025-02129-9","DOIUrl":"https://doi.org/10.1038/s41386-025-02129-9","url":null,"abstract":"<p><p>Working memory relies on synchronised network oscillations involving complex interplay between pyramidal cells and GABAergic interneurons. NMDA receptor (NMDAR) antagonists influence both network oscillations and working memory, but the relationship between these two consequences has not been elucidated. This study aimed to determine the effect of NMDAR antagonists on network oscillations during a working memory task in mice, and the contribution of the GluN2D receptor subunit. After training wildtype (WT) and GluN2D-knockout (KO) mice on the Trial-Unique-Non-match to Location (TUNL) touchscreen task of working memory, recording electrodes were implanted into the prefrontal cortex (PFC) and hippocampus. Mice were challenged with either (S)-ketamine (30 mg/kg), (R)-ketamine (30 mg/kg), phencyclidine (PCP, 1 mg/kg), MK-801 (0.3 mg/kg) or saline prior to TUNL testing while simultaneous local field potential recordings were acquired. PCP disrupted working memory accuracy in WT (p = 0.001) but not GluN2D-KO mice (p = 0.79). MK-801 (p < 0.0001), (S)-ketamine (p < 0.0001) and (R)-ketamine (p = 0.007) disrupted working memory accuracy in both genotypes. PCP increased baseline hippocampal gamma (30-80 Hz) power in WT (p = 0.0015) but not GluN2D-KO mice (p = 0.92). All drugs increased baseline gamma power in the PFC in both genotypes (p < 0.05). Low gamma was induced during the maintenance phase of the TUNL task and increased when mice correctly completed the task (p = 0.024). This response-dependent increase in low gamma was disrupted by all drugs. In summary, PCP action involves the GluN2D subunit of the NMDA receptor in the hippocampus to alter baseline gamma power and working memory. Task-induced low gamma activity during maintenance aligns with task performance, and is disrupted by all NMDAR antagonists.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective KOR antagonist alters functional patch sizes in individualized brain system: results from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)","authors":"Hoki Fung,&nbsp;Ruby M. Potash,&nbsp;Andrew Krystal,&nbsp;Diego A. Pizzagalli,&nbsp;Matthew D. Sacchet","doi":"10.1038/s41386-025-02125-z","DOIUrl":"10.1038/s41386-025-02125-z","url":null,"abstract":"In our prior study involving a transdiagnostic sample of individuals with anhedonia, we showed that an 8-week administration of a selective κ-opioid receptor (KOR) antagonist enhanced fMRI ventral striatal activation during reward anticipation in the Monetary Incentive Delay task as compared to a placebo. However, individual differences in brain architecture may limit the translation of this finding to the context of precision medicine. Here, we adopted an individual-specific approach to elucidate the effects of selective KOR antagonism on cortical-subcortical reward circuits in individuals with anhedonia. Sixty-four participants with anhedonia (30 KOR Antagonist, 34 Placebo) who completed both pre- and post- treatment MRI scans in the FAST-MAS study were included in this analysis. Using an individualized-brain-systems-functional-brain-mapping approach, functional networks were mapped at the individual level, and individual-specific cortical patches and subcortical-cortical clusters were obtained. Statistical analyses were conducted to examine the pre- and post-treatment changes in patch and cluster sizes, as well as their relationships with clinical-cognitive measures. ROI analyses revealed a significant patch size decrease in the right medial posterior prefrontal cortex within the frontoparietal control network, and significant size increases in three right subcortical clusters – pallidum, amygdala, and thalamus – within the orbitofrontal-limbic network, following KOR antagonist treatment. In short,&nbsp;we applied recently developed computational neuroimaging approaches to examine changes in the individualized brain systems of FAST-MAS participants before and after eight weeks of KOR antagonist treatment for anhedonia. Our results revealed alterations in functional cortical patch and subcortical-cortical cluster sizes in anhedonia-related brain regions following KOR antagonist treatment.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 9","pages":"1430-1438"},"PeriodicalIF":6.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demand for heroin in rats: effects of non-drug alternative substitutes and complements","authors":"David N. Kearns,&nbsp;Toni Bird,&nbsp;Emma M. Pilz,&nbsp;Kevin Chavez-Lopez,&nbsp;Felipe Rego,&nbsp;Alan Silberberg","doi":"10.1038/s41386-025-02127-x","DOIUrl":"10.1038/s41386-025-02127-x","url":null,"abstract":"Given the central role of economic demand for drugs in substance use disorder, identifying factors that increase or decrease drug value is of high importance. The present study investigated how the concurrent availability of non-drug reinforcers previously shown to be heroin substitutes or complements affected demand for heroin in rats. In Exp. 1, three groups of rats pressed one lever for intravenous heroin infusions on a series of prices that increased over sessions. The groups differed with respect to what they received for pressing a second lever: timeout-from-avoidance (TOA) reinforcers, heroin at a constant low price, or no programmed consequences. The essential value of heroin was significantly reduced in the groups that had either TOA or low-price heroin available on the second lever. Additionally, as the price of heroin on the first lever increased, consumption of TOA reinforcers or low-price heroin infusions increased, confirming that these were substitutes for expensive heroin. In Exp. 2, two groups of rats pressed one lever for heroin infusions on a series of increasing prices. One group could press a second lever for saccharin reinforcers at a constant low price. Concurrent saccharin availability increased demand for heroin in female rats, but not in male rats. Exp. 3 compared demand for saccharin in groups that had or did not have concurrent access to low-price heroin. Concurrent heroin availability caused an increase in estimated saccharin consumption at no cost (Q0), but did not affect elasticity of demand for saccharin. The outcome of Exp. 1 suggests that non-drug means of reducing pain or stress can weaken demand for opioids. Exp. 2 and 3 show that, in contrast, availability of some non-drug alternatives can increase demand for heroin in female rats and that heroin can increase consumption of non-drug alternatives at low price. Overall, these results show, consistent with the contextualized reinforcer pathology model, that opioid value depends on the broader behavioral economic context in which opioids and non-drug alternatives are available.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1896-1903"},"PeriodicalIF":6.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02127-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144037610","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":"Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning","authors":"Liam T. McCrea,&nbsp;Rebecca E. Batorsky,&nbsp;Joshua J. Bowen,&nbsp;Hana Yeh,&nbsp;Jessica M. Thanos,&nbsp;Ting Fu,&nbsp;Roy H. Perlis,&nbsp;Steven D. Sheridan","doi":"10.1038/s41386-025-02123-1","DOIUrl":"10.1038/s41386-025-02123-1","url":null,"abstract":"Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by ≥2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. These compounds comprise a wide range of therapeutic classes with different mechanisms of action, including immunosuppressants, kinase inhibitors, antipsychotics, and epigenetic modulators. Image-based morphological measurements were calculated to measure the degree of ramified vs. ameboid morphotypes as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. For example, identified drugs such as the tyrosine kinase inhibitors lapatinib, alectinib, and lazertinib and the epigenetic modulator vorinostat have been approved for various cancer treatments and are being investigated for other indications; however, they have not been extensively studied in patients for neurodevelopmental and neurodegenerative disorders. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1544-1552"},"PeriodicalIF":6.6,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02123-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030567","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}