Translational Psychiatry最新文献

{"title":"Association between redox dysregulation and vulnerability to cognitive deficits induced by maternal immune activation.","authors":"Francesca McEwan, Chiho Kambara, Jarred M Lorusso, Michael K Harte, Jocelyn D Glazier, Reinmar Hager","doi":"10.1038/s41398-025-03398-0","DOIUrl":"10.1038/s41398-025-03398-0","url":null,"abstract":"<p><p>Exposure to maternal immune activation (MIA) in utero is a major risk factor for neurodevelopmental disorders, including schizophrenia. However, a proportion of individuals are resilient to developing schizophrenia following exposure to MIA, which has also been reported in animal models of MIA. The molecular mechanisms leading to resilient and vulnerable behavioural phenotypes remain poorly understood, and we currently lack reliable blood biomarkers that predict resilience or vulnerability. Redox dysregulation, caused by an imbalance between oxidative stress and antioxidant defence mechanisms, has recently been predicted to be central to the pathogenesis of schizophrenia. Here, we use a poly(I:C)-induced MIA model of schizophrenia to investigate mechanisms underlying cognitive dysfunction and redox dysregulation in resilient and vulnerable individuals. We show that activity of the antioxidant enzyme superoxide dismutase (SOD) was reduced in the plasma of poly(I:C) offspring with a cognitive deficit, in contrast to individuals with typical cognition during both adolescence and adulthood. However, SOD activity in the hippocampus was not significantly different between vulnerable and resilient offspring. In addition, the lipid peroxidation marker malondialdehyde (MDA) and the pro-inflammatory cytokine IL-6 were not differentially expressed within the hippocampus or plasma of vulnerable poly(I:C) offspring. Our results suggest that reduced plasma SOD activity may be a potential blood biomarker to identify resilience or vulnerability to MIA-induced cognitive deficits. Further research is necessary to determine if reduced antioxidant capacity is present in plasma prior to symptom presentation and to understand if this predicts redox dysregulation in the brain.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"184"},"PeriodicalIF":5.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151626","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":"Computational mechanisms underlying multi-step planning deficits in methamphetamine use disorder.","authors":"Claire A Lavalley, Marishka M Mehta, Samuel Taylor, Anne E Chuning, Jennifer L Stewart, Quentin J M Huys, Sahib S Khalsa, Martin P Paulus, Ryan Smith","doi":"10.1038/s41398-025-03390-8","DOIUrl":"10.1038/s41398-025-03390-8","url":null,"abstract":"<p><p>Current theories suggest individuals with methamphetamine use disorder (iMUDs) have difficulty considering long-term outcomes in decision-making, which could contribute to risk of relapse. Aversive interoceptive states (e.g., stress, withdrawal) are also known to increase this risk. The present study analyzed computational mechanisms of planning in iMUDs, and examined the potential impact of an aversive interoceptive state induction. A group of 40 iMUDs and 49 healthy participants completed two runs of a multi-step planning task, with and without an anxiogenic breathing resistance manipulation. Computational modeling revealed that iMUDs had selective difficulty identifying the best overall plan when this required enduring negative short-term outcomes - a mechanism referred to as aversive pruning. Increases in reported craving before and after the induction also predicted greater aversive pruning in iMUDs. These results highlight aversive pruning deficits as a novel mechanism that could promote poor choice in recovering iMUDs and create vulnerability to relapse.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"181"},"PeriodicalIF":5.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143305","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":"Major depressive disorder in children and adolescents is associated with reduced hair cortisol and anandamide (AEA): cross-sectional and longitudinal evidence from a large randomized clinical trial.","authors":"Andreas Walther, Lukas Eggenberger, Rudolf Debelak, Clemens Kirschbaum, Isabelle Häberling, Ester Osuna, Michael Strumberger, Susanne Walitza, Jeannine Baumgartner, Isabelle Herter-Aeberli, Gregor Berger","doi":"10.1038/s41398-025-03401-8","DOIUrl":"10.1038/s41398-025-03401-8","url":null,"abstract":"<p><p>Pediatric major depressive disorder (MDD) represents a leading cause of disability worldwide in children and adolescents, while its underlying pathophysiology remains largely elusive. The endocannabinoid system (ECS) and the hypothalamus-pituitary-adrenal (HPA) axis are considered intertwined regulatory systems crucially implicated in the pathophysiology of depressive disorders. This study explores the cross-sectional and longitudinal association between the ECS, specifically anandamide (AEA), and the HPA axis with its main effector cortisol and MDD status and severity in children and adolescents. Utilizing data from the omega-3-pMDD trial, a phase III Randomized Clinical Trial assessing the efficacy and safety of omega-3 fatty acid supplementation in pediatric MDD, we examined hair AEA and cortisol concentrations in 110 children and adolescents aged 8-17 years, with MDD. Associations between MDD, symptom severity and hair AEA and cortisol concentrations were explored across four measurement time points (baseline, week 6, 24 and 36). Additionally, 127 healthy children and adolescents were examined once to enable cross-sectional comparisons between MDD cases and healthy controls. Baseline comparisons for the 237 children and adolescents showed lower cortisol and AEA levels in hair of children and adolescents with MDD compared to healthy controls. Longitudinal multi-level analysis over all time-points further corroborated negative longitudinal associations between hair cortisol and depressive symptoms in children and adolescents with MDD. Taken together, reduced baseline AEA and cortisol levels emerge as robust biomarker in depressed youth, while the negative longitudinal association between hair cortisol and depression symptoms might provide useful for therapy monitoring purposes. These results hold implications for early detection, diagnosis, and therapeutic response prediction in pediatric MDD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"183"},"PeriodicalIF":5.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143588","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":"RDS-04-010: a novel atypical DAT inhibitor that inhibits cocaine taking and seeking and itself has low abuse potential in experimental animals.","authors":"Omar Soler-Cedeno, Ewa Galaj, Benjamin Klein, Jianjing Cao, Guo-Hua Bi, Amy Hauck Newman, Zheng-Xiong Xi","doi":"10.1038/s41398-025-03391-7","DOIUrl":"10.1038/s41398-025-03391-7","url":null,"abstract":"<p><p>Cocaine use disorder (CUD) is a severe public health problem, and currently, there is no FDA-approved medication for its treatment. Atypical dopamine (DA) transporter (DAT) inhibitors display low addictive liability by themselves and may have therapeutic potential for treatment of psychostimulant use disorders. Here, we report that RDS-04-010, a novel atypical DAT inhibitor that binds to an inward-facing conformation of DAT due to its sulfoxide moiety, displayed distinct pharmacological profiles in animal models of addiction from its sulfide analog, RDS-03-094, a DAT inhibitor that binds to a more outward-facing conformation. Systemic administration of RDS-04-010 dose-dependently inhibited cocaine self-administration, shifted the cocaine self-administration dose-response curve downward, decreased motivation for cocaine seeking under progressive-ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS-04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS-04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. In contrast, RDS-03-094 displayed more cocaine-like reinforcing effects. Its pretreatment upward-shifted both the cocaine self-administration dose-response and optical brain-stimulation reward curves. RDS-03-094 alone was able to reinstate extinguished cocaine-seeking behavior and sustain self-administration during a substitution test. Collectively, these findings suggest that RDS-04-010 is a novel atypical DAT inhibitor with favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. Moreover, this extensive behavioral evaluation further confirms the role that DAT binding conformation plays in the distinctive profiles of atypical DAT inhibitors that prefer the inward facing conformation.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"182"},"PeriodicalIF":5.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143554","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 novel metabolites in children with attention-deficit hyperactivity disorder through metabolome profiling.","authors":"Yi-An Hung, Tien-Chueh Kuo, Yufeng Jane Tseng, Chi-Yung Shang, Susan Shur-Fen Gau","doi":"10.1038/s41398-025-03393-5","DOIUrl":"10.1038/s41398-025-03393-5","url":null,"abstract":"<p><p>Metabolomics research offers promising potential for identifying key metabolites and exploring the pathophysiological underpinnings of attention-deficit hyperactivity disorder (ADHD). However, serum metabolomics in ADHD remains largely uncharted. Our study aimed to search for metabolomic biomarkers in children with ADHD. 70 drug-naïve children diagnosed with ADHD according to DSM-5 criteria and 70 sex-, age-, IQ-matched healthy controls were recruited from the National Taiwan University Hospital. All participants were assessed for clinical and ADHD symptoms using the Clinical Global Impression Severity (CGI-S) and ADHD Rating Scale-IV (ADHDRS-IV), respectively. Serum-based metabolomic profiles were obtained through liquid chromatography-mass spectrometry. We performed the Wilcoxon test for univariate analysis, the orthogonal partial least squares discriminant analysis (OPLS-DA) for multivariate analysis, and Spearman correlation analyses for the associations between identified metabolites and clinical and ADHD measures. In our study, 156 metabolites were identified in peripheral blood samples using an untargeted metabolomics approach, among which cholic acid, homoveratric acid, inosine, and nicotinuric acid were significantly different between ADHD and controls. Children with ADHD had upregulated cholic acid and homoveratric acid levels and downregulated inosine and nicotinuric acid levels compared to controls. Notably, the upregulated metabolites positively correlated, and the downregulated metabolites negatively correlated with CGI-S and ADHDRS-IV scores. These metabolites and their mechanisms suggested that the pathophysiology of ADHD might involve connections between the gut-brain axis, oxidative stress, dopaminergic pathway, and purine salvage pathway. Our findings of four novel metabolite-behavior relationships in children with ADHD enhanced our understanding of the potential pathways underlying the pathophysiological mechanisms of ADHD.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"180"},"PeriodicalIF":5.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143407","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":"White matter microstructure alterations in early psychosis and schizophrenia.","authors":"Tommaso Pavan, Yasser Alemán-Gómez, Raoul Jenni, Pascal Steullet, Zoé Schilliger, Daniella Dwir, Martine Cleusix, Luis Alameda, Kim Q Do, Philippe Conus, Patric Hagmann, Paul Klauser, Ileana Jelescu","doi":"10.1038/s41398-025-03397-1","DOIUrl":"10.1038/s41398-025-03397-1","url":null,"abstract":"<p><p>Studies on schizophrenia feature diffusion magnetic resonance imaging (dMRI) to investigate white matter (WM) anomalies. The heterogeneity in the possible interpretations of typical Diffusion Tensor Imaging (DTI) metrics highlights the importance of increasing their specificity. Here, we characterize WM pathology in early psychosis (EP) and schizophrenia (SZ) with increased specificity using advanced dMRI: Diffusion Kurtosis Imaging and the biophysical model White Matter Tract Integrity - Watson (WMTI-W). This enables us to better characterize WM abnormalities, while preserving good sensitivity to group differences, and relate them to the current literature (ENIGMA-schizophrenia), patient's clinical characteristics and symptomatology. dMRI-derived microstructure features were extracted from all of WM and from individual regions of interest in 275 individuals. 93 subjects diagnosed with EP and 47 with SZ were compared respectively to 135 age-range matched healthy controls (HC). WM DTI diffusivities were higher, while kurtosis was lower in EP vs HC and in SZ vs HC. Differences were more widespread in EP than SZ. The regional alterations found in our cohort matched the DTI patterns found in ENIGMA-schizophrenia. WMTI-W model parameters indicate that the WM alterations in patients come primarily from the extra-axonal compartment, consistent with abnormal myelin integrity in the disease pathology. The direct link between WM alterations and symptomatology is, however, limited.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"179"},"PeriodicalIF":5.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133284","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":"Perceived criticism and depressive symptoms among adults aged 50 years and older: a 17-year population-based cohort study.","authors":"Yanzhi Li, Liwan Zhu, Yang Yang, Caiyun Zhang, Hao Zhao, Jingman Shi, Wenjian Lai, Wenjing Zhou, Guangduoji Shi, Wanxin Wang, Lan Guo, Ciyong Lu","doi":"10.1038/s41398-025-03322-6","DOIUrl":"10.1038/s41398-025-03322-6","url":null,"abstract":"<p><p>The longitudinal association between perceived criticism and depressive symptoms has not been fully elucidated in older adults. We aimed to explore the above association and the modifying role of sex in older adults. Data were from the English Longitudinal Study of Ageing (waves 1-9; 2002-2019). Depressive symptoms were assessed with the 8-item version of the Center for Epidemiologic Studies-Depression Scale, and a cut-off value of ≥4 was used to define clinically significant depressive symptoms. We included participants aged ≥50 years and without depressive symptoms at baseline, and established four dynamic prospective cohorts to explore the associations of perceived criticism from spouses (n = 8155), children (n = 9049), other immediate family members (OIFM, n = 9370), and friends (n = 9736) with depressive symptoms, respectively. In the full-adjusted model, compared with perceived no spouse criticism, perceived some (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.18-1.55) and a lot (HR, 2.24; 95% CI, 1.85-2.72) were associated with higher risks of depressive symptoms, but perceived a little was not (HR, 1.05; 95% CI, 0.92-1.20). Compared with perceived no child criticism, perceived a little (HR, 1.24; 95% CI, 1.12-1.36), some (HR, 1.50; 95% CI, 1.33-1.68), and a lot (HR, 2.02; 95% CI, 1.62-2.52) were associated with higher risks of depressive symptoms, and perceived criticism from OIFM and friends showed similar results. Sex significantly modified the above associations, and females were more susceptible to four types of perceived criticism than males. Our findings emphasize the benefits of reducing criticism of older adults in preventing their depressive symptoms.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"178"},"PeriodicalIF":5.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133283","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":"First evidence of an anxiety-like behavior and its pharmacological modulation in a molluscan model organism, Lymnaea stagnalis.","authors":"Veronica Rivi, Pierfrancesco Sarti, Istvan Fodor, Zsolt Pirger, Joris M Koene, Luca Pani, Anuradha Batabyal, Ken Lukowiak, Johanna Maria Catharina Blom, Fabio Tascedda, Cristina Benatti","doi":"10.1038/s41398-025-03399-z","DOIUrl":"10.1038/s41398-025-03399-z","url":null,"abstract":"<p><p>Anxiety, a behavioral consequence of stress, has been characterized in humans and some vertebrates but remains largely unexplored in invertebrates. Here, we demonstrate that after being exposed to fish water, which simulates the presence of predators, pond snails (Lymnaea stagnalis) exhibit a series of sustained fear responses. These include increased aerial respiration, changes in righting behavior, and reduced escape responses. Notably, these behaviors persist even after the stressor (fish water) is removed, indicating that they likely represent an anxiety-like state rather than a simple conditioned reflex. Additionally, exposure to fish water enhances long-term memory formation for the operant conditioning of aerial respiration, suggesting that the predator scent potentially induces a state of heightened alertness, which enhances memory consolidation processes. Furthermore, when snails experience fish water alongside an appetitive stimulus (carrot), they form configural learning-a higher form of learning - where the appetitive stimulus now triggers a fear response instead of eliciting feeding. Importantly, the anxiolytic drug alprazolam prevents these anxiety-like responses. Through dose-response experiments, we found that alprazolam at a concentration of 0.1 µM for 15 min effectively counteracts predator-induced anxiety without causing sedation. This treatment also prevents the effects of predator cues on learning and memory. However, consistent with data from vertebrates - alprazolam induces anterograde amnesia, impairing the formation of new memories for up to 3 h after treatment, though it does not cause long-term memory deficits. Overall, this is the first study showing that a molluscan model organism exhibits anxiety-like behaviors similar to those seen in vertebrates, and these behaviors can be mitigated by an anti-anxiety drug. This suggests that fundamental anxiety mechanisms are evolutionarily conserved across species. By using this simple invertebrate model, our research offers new insights into the biological basis of anxiety and sets the stage for future pharmacological studies.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"177"},"PeriodicalIF":5.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128813","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":"Psychiatric and cognitive function in patients with serotonin producing neuroendocrine tumors.","authors":"Maryse J Luijendijk, Margot E T Tesselaar, Huub H van Rossum, Martijn van Faassen, Catharina M Korse, Wieke H M Verbeek, Jocelyn R Spruit, Pernilla C Scheelings, Eva H Hooghiemstra, Ido P Kema, Henricus G Ruhé, Sanne B Schagen, Froukje E de Vries","doi":"10.1038/s41398-025-03272-z","DOIUrl":"10.1038/s41398-025-03272-z","url":null,"abstract":"<p><p>Cognitive and psychiatric problems are common in cancer patients, but literature on patients with neuroendocrine tumors (NET) is scarce. In a subset of these patients, the tumor produces serotonin, causing physical symptoms known as carcinoid syndrome. This peripheral overproduction of serotonin may cause central depletion of its precursor tryptophan, potentially resulting in cognitive and psychiatric problems. Therefore, we investigated cognitive and psychiatric function in patients with a serotonin overproduction and the association with this serotonin overproduction. Eighty-one patients with a serotonin-producing metastatic ileal NET underwent standardized neuropsychological and psychiatric assessment. Blood and urine samples were collected to determine concentrations of serotonin, its precursor tryptophan, and metabolite (5-HIAA). Multivariate normative comparison was applied to determine the prevalence of cognitive impairment. Separate linear regressions of serotonin, tryptophan, and 5-HIAA concentrations on cognitive function, depressive symptoms, and anxiety symptoms were performed, corrected for age, sex, education, and/or duration of illness. We found an 11% prevalence of cognitive impairment and a 20% prevalence of psychiatric disorders. Cognitive function was not related to measures of peripheral serotonin production. Unexpectedly, depressive symptoms were significantly associated with lower serum serotonin concentrations and elevated serum tryptophan concentrations. Cognitive symptoms of anxiety were also associated with elevated tryptophan concentrations. Concluding, cognitive or psychiatric problems occur in a minority of patients with NET and cannot be explained by tryptophan depletion following tumor-related serotonin production.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"176"},"PeriodicalIF":5.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120937","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":"Computational modelling and neural correlates of reinforcement learning following three-week escitalopram: a double-blind, placebo-controlled semi-randomised study.","authors":"Christelle Langley, Graham K Murray, Sophia Armand, Franziska Knolle, Rudolf N Cardinal, Annette Johansen, Peter S Jensen, Jianfeng Feng, Dea S Stenbæk, Gitte M Knudsen, Patrick M Fisher, Barbara J Sahakian","doi":"10.1038/s41398-025-03392-6","DOIUrl":"10.1038/s41398-025-03392-6","url":null,"abstract":"<p><p>Reinforcement learning is a fundamental aspect of adaptive behaviour, since it involves the acquisition and updating of associations between actions and their outcomes based on the rewarding or punishing consequences. Acute experimental manipulations of serotonin have provided compelling evidence for its role in reinforcement learning. However, it remains unknown how more chronic manipulation of serotonin, which holds greater clinical relevance, affects reinforcement learning and the underlying neural mechanisms. Consequently, we aimed to investigate the effect of a three-week administration of the SSRI, escitalopram, on a reinforcement learning paradigm during functional magnetic resonance imaging. The study used a double-blind, placebo-controlled design with 64 healthy volunteers. Participants were semi-randomised, ensuring matched groups for age, sex and intelligence quotient (IQ), to receive either 20 mg of escitalopram (n = 32) or placebo (n = 32) for at least 21 days. We analysed group differences in reinforcement learning using both analysis of covariance as well as innovative hierarchical Bayesian modelling of the reinforcement learning task. Escitalopram reduced learning from punishment during punishment trials. A key novel finding was that there was decreased activation of the intraparietal sulcus in the escitalopram group when compared to the placebo group during reward trials. The involvement of the intraparietal sulcus suggests that escitalopram affects the encoding of value outcome, which may lead to reduced reinforcement sensitivity, and thereby impacting adaptive learning from feedback. Understanding these mechanisms may help to optimize SSRI treatment to mitigate clinical symptoms and improve quality of life for neuropsychiatric patients, by elucidating serotonin's effects on affect, cognition, and behaviour.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"15 1","pages":"175"},"PeriodicalIF":5.8,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12095678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120936","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}