Neuropsychopharmacology最新文献

{"title":"Early postnatal NMDA receptor ablation in cortical interneurons impairs affective state discrimination and social functioning","authors":"Juan M. Uehara, Martina Gomez Acosta, Estefanía P. Bello, Juan E. Belforte","doi":"10.1038/s41386-025-02051-0","DOIUrl":"10.1038/s41386-025-02051-0","url":null,"abstract":"Emotion recognition is fundamental for effective social interactions among conspecifics. Impairments in affective state processing underlie several neuropsychiatric disorders, including schizophrenia, although the neurobiological substrate of these deficits remains unknown. We investigated the impact of early NMDA receptor hypofunction on socio-affective behaviors. Male mice lacking NMDA receptors in GABAergic interneurons of cerebral and hippocampal cortices from an early postnatal age (interNMDAr-KO mutants) were evaluated in affective state discrimination, social preference and social novelty preference, hierarchy and dominance, aggression and territoriality, and long-term social interaction. We show that interNMDAr-KO mice failed to discriminate conspecifics based on their affective states, unlike control littermates, while exhibiting an intact preference for social stimuli over inanimate objects. This discrimination deficit was observed regardless of whether affective valences were manipulated positively or negatively, via a palatable reward or social defeat, respectively. Additionally, interNMDAr-KO mice failed to establish a normal social hierarchy, consistently assuming subordinate roles against control littermates, and presented an abnormal response to conspecifics in the resident-intruder test. Finally, mice lacking NMDA receptors in GABAergic interneurons exhibited social withdrawal following exposure to unfamiliar conspecifics in a custom setting designed to monitor social behavior over extended time periods. This deficit was reversed by subchronic clozapine treatment. Our study thoroughly assessed the impact of a pathophysiological manipulation relevant to schizophrenia on social behavior in mice. Overall, this study provides evidence demonstrating that altered NMDAr-dependent development of cortical and hippocampal interneurons impairs affective state discrimination and leads to deficits in social functioning and long-term sociality.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 7","pages":"1119-1129"},"PeriodicalIF":6.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008798","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":"Polygenic overlap with granulocyte counts identifies novel loci for clozapine metabolism and clozapine-induced agranulocytosis","authors":"Elise Koch, Alexey A. Shadrin, Nadine Parker, Siobhan K. Lock, Robert L. Smith, Oleksandr Frei, Anders M. Dale, Srdjan Djurovic, Espen Molden, Kevin S. O´Connell, Ole A. Andreassen","doi":"10.1038/s41386-025-02054-x","DOIUrl":"10.1038/s41386-025-02054-x","url":null,"abstract":"While clozapine is the most effective antipsychotic drug, its use is limited due to hematological adverse effects involving the reduction of granulocyte counts with potential life-threatening agranulocytosis. It is not yet possible to predict or prevent the risk of agranulocytosis, and the mechanisms are unknown but likely related to clozapine metabolism. Genome-wide association studies (GWASs) of clozapine metabolism and clozapine-induced agranulocytosis have identified few genetic loci. We used the largest available GWAS summary statistics of clozapine metabolism (clozapine-to-norclozapine ratio) and clozapine-induced agranulocytosis, applying the conditional false discovery rate (condFDR) method to increase power for genetic discovery by conditioning on granulocyte counts variants. To investigate potential causal effects of shared loci, we performed Mendelian Randomization analyses. After conditioning on granulocyte counts, we identified two novel loci associated with clozapine-to-norclozapine ratio. These loci were significantly associated with clozapine metabolism in a validation sample of 392 clozapine-treated individuals. For clozapine-induced agranulocytosis, five loci were identified after conditioning on granulocyte counts. These five loci were significantly associated with reduced granulocyte counts in a small independent sample of clozapine-treated individuals. Genetic liability to slow clozapine metabolism (high clozapine-to-norclozapine ratio) showed evidence of a causal effect on reduced neutrophil counts, and genetic liability to low neutrophil counts exhibited weak evidence of a causal effect on clozapine-induced agranulocytosis. Our findings of shared genetic variants associated with clozapine metabolism and granulocyte counts may form the basis for developing prediction models for clozapine-induced agranulocytosis.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"947-955"},"PeriodicalIF":6.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008805","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":"Examining memory reconsolidation as a mechanism of nitrous oxide’s antidepressant action","authors":"Ella Williams, Ursule Taujanskaite, Sunjeev K. Kamboj, Susannah E. Murphy, Catherine J. Harmer","doi":"10.1038/s41386-024-02049-0","DOIUrl":"10.1038/s41386-024-02049-0","url":null,"abstract":"There is an ongoing need to identify novel pharmacological agents for the effective treatment of depression. One emerging candidate, which has demonstrated rapid-acting antidepressant effects in treatment-resistant groups, is nitrous oxide (N2O)—a gas commonly used for sedation and pain management in clinical settings and with a range of pharmacological effects, including antagonism of NMDA glutamate receptors. A growing body of evidence suggests that subanaesthetic doses of N2O (50%) can interfere with the reconsolidation of maladaptive memories in healthy participants and across a range of disorders. Negative biases in memory play a key role in the onset, maintenance, and recurrence of depressive episodes, and the disruption of affective memory reconsolidation is one plausible mechanism through which N2O exerts its therapeutic effects. Understanding N2O’s mechanisms of action may facilitate future treatment development in depression. In this narrative review, we introduce the evidence supporting an antidepressant profile of N2O and evaluate its clinical use compared to other treatments. With a focus on the specific memory processes that are thought to be disrupted in depression, we consider the effects of N2O on memory reconsolidation and propose a memory-based mechanism of N2O antidepressant action.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 4","pages":"609-617"},"PeriodicalIF":6.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008803","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":"In memoriam: Dr. Thomas Lehner","authors":"J. John Mann, Joshua A. Gordon","doi":"10.1038/s41386-024-02048-1","DOIUrl":"10.1038/s41386-024-02048-1","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 4","pages":"718-718"},"PeriodicalIF":6.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-02048-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984318","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 impact of ovulation-suppressing contraceptives on behavioral and functional difficulties in borderline personality disorder","authors":"Seyma Katrinli, Alex O. Rothbaum, Raneeka DeMoss, William C. Turner, Ben Hunter, Abigail Powers, Vasiliki Michopoulos, Alicia K. Smith","doi":"10.1038/s41386-024-02045-4","DOIUrl":"10.1038/s41386-024-02045-4","url":null,"abstract":"Borderline Personality Disorder (BPD) is characterized by rapidly shifting emotional, interpersonal, and behavioral symptoms, often co-morbid with mood and anxiety disorders. Females are more likely to be diagnosed with BPD than males and exhibit greater functional impairment. Hormonal fluctuations may influence the manifestation of BPD symptoms. Here, we investigated the influence of ovulation-suppressing contraceptives on behavioral and functional difficulties in BPD. The sample included 348 females ages 18-50 undergoing residential treatment for psychiatric disorders, with 131 having a BPD diagnosis. Patients were categorized by their contraceptive method: Ovulation-suppressing contraceptives (N = 145) and naturally cycling (N = 203). Interaction models tested the impact of ovulation-suppressing contraceptives on the relationship between BPD diagnosis and behavioral and functional difficulties at admission and discharge, assessed by the four Behavior and Symptom Identification Scale (BASIS-32) domains: difficulties in relationships, daily living, depression/anxiety, and impulsivity. Females with a BPD diagnosis were more likely to use ovulation-suppressing contraceptives compared to those without BPD (p = 0.04). However, ovulation-suppressing contraceptive use was not associated with behavioral and functional difficulties at admission, discharge, or over time. Ovulation-suppressing contraceptives moderated the association between BPD diagnosis and difficulties in relationships (p = 0.004), difficulties in daily living (p = 0.01), and depression/anxiety symptoms (p = 0.004). Specifically, patients with BPD experienced more behavioral and functional difficulties only if naturally cycling, whereas patients without BPD showed higher symptom severity only if using ovulation-suppressing contraceptives. Our findings suggest that the impact of ovulation-suppressing contraceptives on behavioral and functional difficulties varies depending on BPD diagnosis and underscores the need for further clinical studies.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"841-848"},"PeriodicalIF":6.6,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-02045-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971701","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":"Multivariate patterns among multimodal neuroimaging and clinical, cognitive, and daily functioning characteristics in bipolar disorder","authors":"Viktoria Damgaard, Lydia Fortea, Johanna M. Schandorff, Julian Macoveanu, Bethany Little, Peter Gallagher, Gitte M. Knudsen, Lars V. Kessing, Kamilla W. Miskowiak","doi":"10.1038/s41386-024-02047-2","DOIUrl":"10.1038/s41386-024-02047-2","url":null,"abstract":"Individuals with bipolar disorder (BD) show heterogeneity in clinical, cognitive, and daily functioning characteristics, which challenges accurate diagnostics and optimal treatment. A key goal is to identify brain-based biomarkers that inform patient stratification and serve as treatment targets. The objective of the present study was to apply a data-driven, multivariate approach to quantify the relationship between multimodal imaging features and behavioral phenotypes in BD. We pooled structural, task and resting-state functional magnetic resonance imaging (MRI), and clinical, cognitive, and functioning data from 167 fully or partly remitted patients with BD from three studies conducted at the same site. We performed canonical correlation analysis (CCA) to investigate multivariate relations among the 56 imaging and 23 behavioral features in patients. Data from 46 matched healthy controls were included for covariate-adjusted standardization of patients’ scores and for group comparisons. The imaging and behavioral data sets showed a strong canonical correlation (r = 0.84, p = .004). Among the behavioral variables, cognitive test scores across psychomotor speed, verbal memory, and verbal fluency were associated with the multimodal imaging variate comprising task activation within the dorsolateral prefrontal cortex and supramarginal gyrus, also when other clinical and daily functioning variables were considered. Task activation within the dorsal prefrontal and parietal cognitive control areas constitutes a potential pro-cognitive treatment target.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"976-982"},"PeriodicalIF":6.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-02047-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951938","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":"Epac2 activation drives calcium permeable-AMPA receptor accumulation, fueling the incubation of cocaine craving","authors":"Changyong Guo, Yao-Ying Ma","doi":"10.1038/s41386-024-02043-6","DOIUrl":"10.1038/s41386-024-02043-6","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 4","pages":"618-619"},"PeriodicalIF":6.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951874","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 relationship between electric field strength induced by electroconvulsive therapy and cognitive and antidepressant outcomes","authors":"Dore Loef, Miklos Argyelan, Henricus G. Ruhé, Dominique S. Scheepens, Robert A. Schoevers, Indira Tendolkar, Eric van Exel, Jeroen A. van Waarde, Guido A. van Wingen, Joey P. A. J. Verdijk, Esmée Verwijk, Annemiek Dols, Philip F. P. van Eijndhoven","doi":"10.1038/s41386-024-02050-7","DOIUrl":"10.1038/s41386-024-02050-7","url":null,"abstract":"Electroconvulsive therapy (ECT) is an effective treatment for depression but is often associated with cognitive side effects. In patients, ECT-induced electric field (E-field) strength across brain regions varies significantly due to anatomical differences, which may explain individual differences in cognitive side effects. We examined the relationship between regional E-field strength and change in verbal fluency score (i.e., category fluency animals score from pre- to 1 week post-ECT; as key proxy of cognitive side effects) across different electrode placements in depressed patients. Secondary, we examined the relationship between regional E-field strength and depression outcome. Using T1 magnetic resonance imaging, we performed E-field modeling in a total of 109 patients. Linear mixed models were executed to analyze the relationship between E-field strength across all 118 brain regions and both cognitive and depression outcomes, while correcting for nuisance variables (e.g., age, total number of ECT sessions, and study cohort). We found that a higher E-field strength was significantly associated with a higher decline in verbal fluency (n = 71, false discovery rate [FDR] corrected p < 0.01) in several brain regions in the left hemisphere (e.g., temporal gyrus and operculum cortex). Moreover, numerous significant associations were found only in the 24 patients treated with right unilateral ECT. No significant relationships were found between regional E-field strength and depression outcome. In conclusion, significant associations between verbal fluency and E-field strength were found in areas crucial for linguistic processing and semantic memory. Our findings underscore the importance of considering individualized dosing strategies to optimize cognitive outcome in ECT, while maintaining its antidepressant efficacy.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 7","pages":"1102-1118"},"PeriodicalIF":6.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085521","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":"Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study","authors":"Ryan Terry-Lorenzo, Daniel Albrecht, Sabrinia Crouch, Richard Wong, Gordon Loewen, Nagdeep Giri, Heather Skor, Kelly Lin, Christine M. Sandiego, Meghan Pajonas, Eugenii A. Rabiner, Roger N. Gunn, David S. Russell, Dietrich Haubenberger","doi":"10.1038/s41386-024-02046-3","DOIUrl":"10.1038/s41386-024-02046-3","url":null,"abstract":"Positron emission tomography (PET) is frequently used to obtain target occupancy (%TO) of central nervous system (CNS) drug candidates during clinical development. Obtaining %TO with PET can be particularly powerful when the %TO associated with efficacy is known for a protein target. Using the radiotracer [18F]AV-133, the relationship between plasma concentration (PK) and %TO of NBI-750142, an experimental inhibitor of the vesicular monoamine transporter type 2 (VMAT2) was obtained in both nonhuman primate (NHP) and human. This work established [18F]AV-133 PET as capable of providing a VMAT2 inhibitor PK-%TO relationship that translated from NHP to human. To establish the VMAT2%TO benchmark, PET was performed in NHP with NBI-98782, the main active metabolite of valbenazine, and this PK-%TO relationship was used to estimate VMAT2%TO at NBI-98782 exposures associated with valbenazine therapeutic effects in the treatment of tardive dyskinesia (TD). This work defined 85–90% as the VMAT2%TO achieved by exposures associated with daily dosing with 80 mg valbenazine, a dosing regimen known to exhibit a large effect size in the treatment of TD and in the treatment of chorea associated with Huntington’s Disease. NBI-750142 was estimated to achieve 36–78% VMAT2 target occupancy at acceptable doses, indicating potential inferiority in conferring clinical benefit compared to valbenazine. It is recommended that the %TO benchmark of valbenazine derived from [18F]AV-133 PET serve as a gold standard biomarker to evaluate novel VMAT2 inhibitors undergoing clinical development.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 7","pages":"1093-1101"},"PeriodicalIF":6.6,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-02046-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932521","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":"In remembrance of Herbert Pardes, M.D. July 7, 1934–April 30, 2024","authors":"Peter J. Tarr, Judith M. Ford","doi":"10.1038/s41386-024-02037-4","DOIUrl":"10.1038/s41386-024-02037-4","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 4","pages":"717-717"},"PeriodicalIF":6.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-024-02037-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915279","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}