Neuropsychopharmacology最新文献

{"title":"Evenamide reverses schizophrenia-related dysfunction in a neurodevelopmental animal model","authors":"Daniela L. Uliana, Rachel A. Walsh, Debora Fabris, Anthony A. Grace","doi":"10.1038/s41386-025-02188-y","DOIUrl":"10.1038/s41386-025-02188-y","url":null,"abstract":"Schizophrenia is characterized by positive, negative, and cognitive symptoms. However, current D2-based antipsychotic drugs only address primarily positive symptoms. Limbic hippocampus hyperexcitability is a key pathological state of schizophrenia, representing an ideal therapeutic target. Evenamide is a selective voltage-gated sodium channel blocker that reduces neuronal hyperexcitability. We examined the effect of acute evenamide treatment on the hyperdopaminergic state, hippocampal hyperexcitability, social deficits, and recognition memory in the methylazoxymethanol acetate (MAM) neurodevelopmental model. Male and female Sprague-Dawley offspring from dams treated with saline or MAM on gestational day 17 were tested as adults (postnatal day >65). Electrophysiological recordings were made in the ventral tegmental area (VTA) and ventral hippocampus (vHipp) and social approach and novel object recognition were tested. Evenamide (3 mg/kg i.p.) normalized the number of spontaneously active DA neurons in the VTA of female and male MAM rats and reduced pyramidal neuron hyperactivity in the vHipp. The hyperdopaminergic state in the VTA of female and male MAM rats was also rescued by local evenamide injection in the vHipp (1 µM). Systemic evenamide also reversed the recognition memory impairment of female and male MAM rats. For social deficits, only male MAM rats exhibit a reduced social sniffing time that was normalized by evenamide. These findings suggest that evenamide’s efficacy in downregulating the hyperdopaminergic state, social deficits, and recognition memory impairment may result from its ability to attenuate vHipp hyperexcitability. Therefore, evenamide could offer a novel therapeutic strategy that is capable of addressing positive, cognitive, and negative symptoms of schizophrenia.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1631-1642"},"PeriodicalIF":6.6,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144791804","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":"A biological phenotype of suicide attempt in adolescents with nonsuicidal self-injury: a machine-based learning approach","authors":"Erik Fink, Corinna Reichl, Stefan Lerch, Julian Koenig, Michael Kaess","doi":"10.1038/s41386-025-02176-2","DOIUrl":"10.1038/s41386-025-02176-2","url":null,"abstract":"Suicide attempts (SA) are a common risk in adolescents with non-suicidal self-injury (NSSI). In the present study, we investigated whether a set of biological markers contributed (above clinical features) to the distinction of adolescents with NSSI and SA from those with NSSI alone using machine-based learning approaches. Female adolescents engaging in NSSI (n = 161) were recruited from our outpatient clinic for risk-taking and self-harming behavior (AtR!Sk). Different machine-based learning models (logistic regression, elastic net regression, random forests, gradient boosted trees) with repeated cross-validation were applied. We tested whether a) the full set of neurobiological markers, b) a reduced set including preselected markers based on existing evidence (CRP, interleukin-6, salivary cortisol, DHEA-S, TSH, dopamine, norepinephrine, ACTH), and c) a model with only depressive symptoms and age could distinguish between the two groups (NSSI + SA vs. NSSI alone). Depressive symptoms and age were included as covariates in the reduced set to account for their potential predictive effects. The reduced set of neurobiological markers showed poor to fair predictive performance (AUC between 0.62 and 0.72) for SA depending on the model. Predictors with the highest predictive value were high DHEA-S (OR = 1.47, 95% CI = 1.04–2.09) and low TSH (OR = 0.68, 95% CI = 0.48–0.97). Complex models slightly outperformed simpler ones and feature selection modestly increased predictive performance. The study may suggest a future potential of biomarkers for the assessment of suicide risk among adolescents with NSSI. Further research is needed to replicate these findings longitudinally.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1817-1826"},"PeriodicalIF":6.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02176-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746990","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":"Does cannabidiol reduce the adverse effects of cannabis in schizophrenia? A randomised, double-blind, cross-over trial","authors":"Edward Chesney, Dominic Oliver, Ananya Sarma, Ayşe Doğa Lamper, Ikram Slimani, Millie Lloyd, Alex M. Dickens, Michael Welds, Matilda Kråkström, Irma Gasparini-Andre, Matej Orešič, Will Lawn, Natavan Babayeva, Tom P. Freeman, Amir Englund, John Strang, Philip McGuire","doi":"10.1038/s41386-025-02175-3","DOIUrl":"10.1038/s41386-025-02175-3","url":null,"abstract":"In patients with schizophrenia, cannabis use exacerbates symptoms and can lead to a relapse of psychosis. Some experimental studies in healthy volunteers suggest that pre-treatment with cannabidiol (CBD) may reduce these effects, but others do not. Here, we investigated whether pre-treatment with CBD ameliorates the acute adverse effects of cannabis in patients with schizophrenia. Participants (n = 30) had schizophrenia or schizoaffective disorder plus a comorbid cannabis use disorder. In a double-blind, randomised, placebo-controlled, crossover trial, participants received oral CBD 1000 mg or placebo three hours before inhaling vaporised cannabis (containing Δ9-tetrahydrocannabinol (THC) 20–60 mg). The primary outcome was delayed verbal recall measured with the Hopkins Verbal Learning Test-Revised. We also measured psychotic symptoms with the Positive and Negative Syndrome Scale (PANSS) – positive subscale. Delayed verbal recall after cannabis administration was 3.5 words (95% confidence interval [CI]: 2.5–4.5) following pre-treatment with CBD, compared to 4.8 words (95% CI: 3.9 to 5.8) following pre-treatment with placebo (mean difference [MD] = −1.3 [95% CI: −2.0 to −0.6]; p = 0.001). After CBD pre-treatment, inhalation of cannabis was associated with an increase in PANSS-P score of 5.0 (95% CI: 3.6 to 6.5), compared to 2.9 (95% CI: 1.5 to 4.3) following pre-treatment with placebo (MD = 2.2 [95% CI: 0.6 to 3.7]; p = 0.01). Administration of CBD did not have a significant effect on plasma concentration of THC or its active metabolite, 11-hydroxy-THC. In patients with schizophrenia and a comorbid cannabis use disorder, pre-treatment with CBD did not attenuate the acute effects of cannabis on memory impairment or psychotic symptoms, but appeared to exacerbate them. The study was registered on Clinicaltrials.gov (NCT04605393).","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 12","pages":"1759-1767"},"PeriodicalIF":6.6,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02175-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700960","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":"Timing matters: modeling the effects of gestational cannabis exposure on social behavior and microglia in the developing amygdala","authors":"Aidan L. Pham, Ashley E. Marquardt, Kristen R. Montgomery, Karina N. Sobota, Margaret M. McCarthy, Jonathan W. VanRyzin","doi":"10.1038/s41386-025-02173-5","DOIUrl":"10.1038/s41386-025-02173-5","url":null,"abstract":"Cannabis is the most frequently used illicit drug during pregnancy, with use steadily increasing in the United States as legalization and decriminalization expand to more states. Many pregnant individuals use cannabis to reduce adverse symptoms of pregnancy, considering it to be less harmful than other pharmaceuticals or alcohol. The primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), is a partial agonist of the candidate receptors of the endocannabinoid (eCB) system cannabinoid receptor 1 (CB1R) and 2 (CB2R). However, whether it perturbs neural development of the fetus is poorly understood. Previously we have shown that androgen mediated eCB tone in the developing amygdala promotes microglial phagocytosis of newborn astrocytes which has enduring consequences on the neural circuits regulating sex differences in social behavior. Microglia are the resident immune cells of the brain and express both CB1R and CB2R, making them likely targets of modulation by THC. It is also plausible that exposure to THC at differing gestational timepoints can result in distinct outcomes, as is the case with alcohol exposure. To model human cannabis use during either late or early pregnancy, we exposed rodents to THC either directly during the early postnatal period via intraperitoneal (IP) injection or in utero during the prenatal period via dam subcutaneous (SC) injection respectively. Here we show that postnatal THC exposure results in sex specific changes in microglial phagocytosis during development as well as social behavior during the juvenile period. Interestingly prenatal exposure to THC resulted in inverse changes to phagocytosis and social behavior. These findings highlight the differential effects of THC exposure across gestation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1655-1664"},"PeriodicalIF":6.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02173-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700961","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":"Safety and tolerability of multiple sublingual microdoses of 5-MeO-DMT in adults with moderate symptoms of depression and/or anxiety: a randomized, double-blind, placebo-controlled study","authors":"Maria Beatriz Bistue Millón, Laura Noguera, Diana Bruno, Luciana Vita, Mariana Zanino, Diego E. Kassuha, Javier E. Ortiz, Gabriela E. Feresin, Paola Díaz-Dellavalle, Lorena Orosco, M. Agustina Garcés, Pablo Diez, Sergio G. Albarracín, Martin A. Bruno","doi":"10.1038/s41386-025-02167-3","DOIUrl":"10.1038/s41386-025-02167-3","url":null,"abstract":"This Phase I clinical trial is the first to rigorously evaluate the safety, tolerability, and pharmacokinetics of a novel sublingual formulation of 5-MeO-DMT, administered at sub-psychedelic doses to adults with moderate to high levels of anxiety and/or depression, without formal psychiatric diagnosis or ongoing treatment. Using a double-blind, placebo-controlled design, participants received a single weekly sublingual dose of 5-MeO-DMT (6 mg, 9 mg, or 12 mg) or placebo over four weeks. The compound was well tolerated across all groups, with no significant adverse events or signs of organ toxicity; mild side effects such as nausea and headache were transient and self-resolving. Pharmacokinetic analyses showed rapid absorption, with peak plasma concentrations occurring within a median of 20 min and no evidence of drug accumulation. Neurophysiological assessments revealed dose-dependent modulation of brain activity without eliciting full psychedelic effects, supporting the feasibility of repeated sub-psychedelic dosing. Participants remained cognitively and behaviorally stable, maintaining their usual daily activities and social interactions. This study marks a pivotal advancement in the clinical exploration of psychedelic compounds, highlighting the potential of 5-MeO-DMT as a safe, fast-acting compound with favorable tolerability and emerging as a promising candidate for future therapeutic applications. These findings provide critical groundwork for future trials targeting psychiatric populations, positioning 5-MeO-DMT as a novel, fast-acting therapeutic strategy with broad clinical relevance. ClinicalTrials.gov: NCT06816667","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 11","pages":"1715-1723"},"PeriodicalIF":6.6,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02167-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639599","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":"M6A RNA epitranscriptome dynamics linked to major depressive disorder and suicide risk","authors":"Bhaskar Roy, Yogesh Dwivedi","doi":"10.1038/s41386-025-02165-5","DOIUrl":"10.1038/s41386-025-02165-5","url":null,"abstract":"Major depressive disorder (MDD) is the most prevalent psychiatric disorder. MDD patients are at substantially increased risk of dying by suicide. The molecular mechanisms associated with MDD and associated suicide are not clearly understood, which impedes the development of novel therapeutics. N6-methyladenosine (m6A) is the most prevalent epitranscriptomic mark on mRNA and plays significant roles in various physiological processes. This study investigated m6A RNA methylation and its potential contributions to MDD pathogenesis and associated suicide risk. High-throughput microarray analysis in the dorsolateral prefrontal cortex (dlPFC) of MDD subjects (n = 49) and non-psychiatric controls (n = 49) identified 1290 significantly hypermethylated and 6842 hypomethylated transcripts, with most m6A sites enriched in coding sequences. Chromosome-wide analysis showed hypermethylation hotspots on chromosomes 1 and 19. In-silico analysis identified enriched AAGA and ACCCA m6A motifs in the MDD group. Expression analysis revealed reduced FTO demethylase and increased METTL3 methyltransferase levels. A majority of M6A hypermethylated genes showed inverse correlation with their expression levels. Functional enrichment of hypermethylated genes highlighted disruptions in molecular pathways relevant to MDD. Comparison of MDD-non-suicide (n = 32) and MDD-suicide (n = 17) identified 6750 transcripts with significant hypermethylation, whereas 6159 transcripts had significant hypomethylation in the MDD-suicide group; of them, 196 hypermethylated genes were explicitly associated with suicide in the MDD group, whereas 38 hypermethylated genes appeared to elevate suicide risk in MDD patients. Also, the MDD-suicide group had distinct neuromolecular pathways associated with these risk genes. Collectively, the findings suggest a critical role for m6A methylation in modulating the molecular networks underlying MDD and suicide susceptibility.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1524-1535"},"PeriodicalIF":6.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02165-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610956","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":"nNOS-expressing neurons in the mPFC mediate depression-related behaviors in mice through pPVT-mPFC projections","authors":"Hai-Ying Liang, Zhi-Bin Zhao, Zhen Liu, James Samsom, Kai-Hong Chen, Ying Chen, Li-Ling Chen, Cheng-Yun Cai, Fang Liu","doi":"10.1038/s41386-025-02163-7","DOIUrl":"10.1038/s41386-025-02163-7","url":null,"abstract":"Depression is one of the most common mental disorders, but its etiology remains poorly understood. Neuronal nitric oxide synthase (nNOS) has been implicated in depression, but the role of nNOS-expressing neurons is still unknown. We used chemogenetic strategies to show that nNOS-expressing neurons in the medial prefrontal cortex (mPFC) are essential for depression-related behaviors. Using electrophysiology, we determined that mPFC nNOS-expressing neurons receive projections from the posterior subregion of the paraventricular thalamic nucleus (pPVT). We show that excitatory projections from the pPVT onto mPFC nNOS-expressing neurons regulate depression-related behaviors. We further explore a mechanism in which activation of mPFC nNOS-expressing neurons leads to the subsequent release of nitric oxide (NO), which enhances the nitrosylation of cyclin-dependent kinase 5 (CDK5). Our data suggest a mechanism for depression involving excitatory pPVT projections onto nNOS-expressing neurons in the mPFC that represents a potential target for future treatments.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1583-1594"},"PeriodicalIF":6.6,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02163-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593722","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":"Distinct subpopulations of parvalbumin neurons participating in divergent prefrontal functions","authors":"Yehong Hu, Xinyang Zhang, Tsz Hei Fong, Tianyu Wang, Jin Zhang, Yujie Zhang, Qiang Zhou","doi":"10.1038/s41386-025-02159-3","DOIUrl":"10.1038/s41386-025-02159-3","url":null,"abstract":"Prefrontal parvalbumin (PV) neurons play crucial roles in various distinct functions, while malfunction of PV-neurons also has critical contributions to various brain diseases, including both psychiatric and neurodegenerative disorders. However, whether the prefrontal cortex (PFC) PV-neurons participating in these functions and malfunctions are distinct subpopulations is not well understood. This question is important for a better understanding of both the basic properties/function of PV-neurons and inhibitory neurons in general, and for potential comorbid occurrence of dysfunctions in disease settings. Here, we analyzed dorsomedial prefrontal cortex (dmPFC) PV-neurons participating in working memory, modulation of conditioned fear memory, and anxiety, regarding their relative localization, electrophysiological properties, and synaptic inputs. In addition, by using activity-dependent tagging method, we examined whether manipulating the dmPFC PV-neurons participating in one function may affect another function as a way to test for potential functional interactions between them. We found that: (1) one single group of dmPFC PV-neurons participating in the two forms of modulation of conditioned fear memory, based on their high overlap in localization and mutual functional interactions with each other. (2) dmPFC PV-neurons participating in fear memory modulation and anxiety are two different subpopulations, with unique electrophysiological properties. (3) dmPFC PV-neurons participating in working memory and fear memory modulation are two different subpopulations, with different synaptic and neuronal properties. These findings provide important insights into the organization of PV-neurons in the PFC and highlight the distinct and non-interacting nature of different PV-subpopulations in the PFC functional diversity.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1502-1514"},"PeriodicalIF":6.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586202","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":"To indulge or enrich: how environmental enrichment affects neurons that promote food seeking","authors":"Pelle Wilbers, Michel C. van den Oever","doi":"10.1038/s41386-025-02166-4","DOIUrl":"10.1038/s41386-025-02166-4","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1465-1466"},"PeriodicalIF":6.6,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565616","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":"High hopes, hard realities: cannabidiol shows no acute effects in youth with alcohol use disorder","authors":"L. Cinnamon Bidwell","doi":"10.1038/s41386-025-02160-w","DOIUrl":"10.1038/s41386-025-02160-w","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 10","pages":"1467-1468"},"PeriodicalIF":6.6,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-025-02160-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562652","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}