Translational Psychiatry最新文献

{"title":"Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder.","authors":"Yasunori Sano, Yasuharu Yamamoto, Manabu Kubota, Sho Moriguchi, Kiwamu Matsuoka, Shin Kurose, Kenji Tagai, Hironobu Endo, Bun Yamagata, Hisaomi Suzuki, Ryosuke Tarumi, Kie Nomoto, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Hajime Tabuchi, Masaru Mimura, Hiroyuki Uchida, Makoto Higuchi, Keisuke Takahata","doi":"10.1038/s41398-024-03107-3","DOIUrl":"10.1038/s41398-024-03107-3","url":null,"abstract":"<p><p>Phosphodiesterase 10 A (PDE10A), a pivotal element of the second messenger signaling downstream of the dopamine receptor stimulation, is conceived to be crucially involved in the mood instability of bipolar I disorder (BD-I) as a primary causal factor or in response to dysregulated dopaminergic tone. We aimed to determine whether striatal PDE10A availability is altered in patients with BD-I and assessed its relationship with the clinical characteristics of BD-I. This case-control study used positron emission tomography (PET) with 2-(2-(3-(4-(2-[¹⁸F]fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([¹⁸F]MNI-659), a radioligand that binds to PDE10A, to examine the alterations of the striatal PDE10A availability in the living brains of individuals with BD-I and their association with the clinical characteristics of BD-I. [¹⁸F]MNI-659 PET data were acquired from 25 patients with BD-I and 27 age- and sex-matched healthy controls. Patients with BD-I had significantly lower PDE10A availability than controls in the executive (F = 8.86; P = 0.005) and sensorimotor (F = 6.13; P = 0.017) subregions of the striatum. Lower PDE10A availability in the executive subregion was significantly associated with a higher frequency of mood episodes in patients with BD-I (r = -0.546; P = 0.007). This study provides the first evidence of altered PDE10A availability in patients with BD-I. Lower PDE10A availability in the executive subregion of the striatum is associated with an increased recurrence risk, suggesting that PDE10A may prevent BD-I relapse. Further studies are required to elucidate the role of PDE10A in BD-I pathophysiology and explore its potential as a treatment target.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"403"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366603","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":"COVID-19 related cognitive, structural and functional brain changes among Italian adolescents and young adults: a multimodal longitudinal case-control study.","authors":"Azzurra Invernizzi, Stefano Renzetti, Christoph van Thriel, Elza Rechtman, Alessandra Patrono, Claudia Ambrosi, Lorella Mascaro, Daniele Corbo, Giuseppa Cagna, Roberto Gasparotti, Abraham Reichenberg, Cheuk Y Tang, Roberto G Lucchini, Robert O Wright, Donatella Placidi, Megan K Horton","doi":"10.1038/s41398-024-03108-2","DOIUrl":"10.1038/s41398-024-03108-2","url":null,"abstract":"<p><p>Coronavirus disease 2019 (COVID-19) has been associated with brain functional, structural, and cognitive changes that persist months after infection. Most studies of the neurologic outcomes related to COVID-19 focus on severe infection and aging populations. Here, we investigated the neural activities underlying COVID-19 related outcomes in a case-control study of mildly infected youth enrolled in a longitudinal study in Lombardy, Italy, a global hotspot of COVID-19. All participants (13 cases, 27 controls, mean age 24 years) completed resting-state functional (fMRI), structural MRI, cognitive assessments (CANTAB spatial working memory) at baseline (pre-COVID) and follow-up (post-COVID). Using graph theory eigenvector centrality (EC) and data-driven statistical methods, we examined differences in EC_delta (i.e., the difference in EC values pre- and post-COVID-19) and Volumetric_delta (i.e., the difference in cortical volume of cortical and subcortical areas pre- and post-COVID) between COVID-19 cases and controls. We found that EC_delta significantly between COVID-19 and healthy participants in five brain regions; right intracalcarine cortex, right lingual gyrus, left hippocampus, left amygdala, left frontal orbital cortex. The left hippocampus showed a significant decrease in Volumetric_delta between groups (p = 0.041). The reduced EC_delta in the left amygdala associated with COVID-19 status mediated the association between COVID-19 and disrupted spatial working memory. Our results show persistent structural, functional and cognitive brain changes in key brain areas associated with olfaction and cognition. These results may guide treatment efforts to assess the longevity, reversibility and impact of the observed brain and cognitive changes following COVID-19.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"402"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366605","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":"Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability.","authors":"Timothy A Fenton, Olivia Y Haouchine, Elizabeth B Hallam, Emily M Smith, Kiya C Jackson, Darlene Rahbarian, Cesar P Canales, Anna Adhikari, Alex S Nord, Roy Ben-Shalom, Jill L Silverman","doi":"10.1038/s41398-024-03077-6","DOIUrl":"10.1038/s41398-024-03077-6","url":null,"abstract":"<p><p>Disruption of SYNGAP1 directly causes a genetically identifiable neurodevelopmental disorder (NDD) called SYNGAP1-related intellectual disability (SRID). Without functional SynGAP1 protein, individuals are developmentally delayed and have prominent features of intellectual disability (ID), motor impairments, and epilepsy. Over the past two decades, there have been numerous discoveries indicating the critical role of Syngap1. Several rodent models with a loss of Syngap1 have been engineered, identifying precise roles in neuronal structure and function, as well as key biochemical pathways key for synapse integrity. Homozygous loss of SYNGAP1/Syngap1 is lethal. Heterozygous mutations of Syngap1 result in a broad range of behavioral phenotypes. Our in vivo functional data, using the original mouse model from the Huganir laboratory, corroborated behaviors including robust hyperactivity and deficits in learning and memory in young adults. Furthermore, we described impairments in the domain of sleep, characterized using neurophysiological data that was collected with wireless, telemetric electroencephalography (EEG). Syngap1^+/- mice exhibited elevated spiking events and spike trains, in addition to elevated power, most notably in the delta power frequency. For the first time, we illustrated that primary neurons from Syngap1^+/- mice displayed: 1) increased network firing activity, 2) greater bursts, 3) and shorter inter-burst intervals between peaks, by utilizing high density microelectrode arrays (HD-MEA). Our work bridges in vitro electrophysiological neuronal activity and function with in vivo neurophysiological brain activity and function. These data elucidate quantitative, translational biomarkers in vivo and in vitro that can be utilized for the development and efficacy assessment of targeted treatments for SRID.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"405"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366634","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":"Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.","authors":"Lei Li, Weijing Kan, Yi Zhang, Tianyi Wang, Feng Yang, Tengfei Ji, Gang Wang, Jing Du","doi":"10.1038/s41398-024-03127-z","DOIUrl":"10.1038/s41398-024-03127-z","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDS_CON), imipramine (IMI)-treated versus CSDS (IMI_CSDS), and NOR-treated versus CSDS (NOR_CSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NOR_CSDS groups and NOR_IMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NOR_CSDS and NOR_IMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"400"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366637","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":"LEAP2, a ghrelin receptor inverse agonist, and its effect on alcohol-related responses in rodents.","authors":"Maximilian Tufvesson-Alm, Cajsa Aranäs, Sebastian Blid Sköldheden, Jesper Vestlund, Christian E Edvardsson, Elisabet Jerlhag","doi":"10.1038/s41398-024-03136-y","DOIUrl":"10.1038/s41398-024-03136-y","url":null,"abstract":"<p><p>The underlying neurobiology of alcohol use disorder (AUD) is complex and needs further unraveling, with one of the key mechanisms being the gut-brain peptide ghrelin and its receptor (GHSR). However, additional substrates of the ghrelin pathway, such as liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR inverse agonist, may contribute to this neurobiological framework. While LEAP2 modulates feeding and reward through central mechanisms, its effects on alcohol responses are unknown. The aim of the present study was therefore to identify the impact of central LEAP2 on the ability of alcohol to activate the mesolimbic dopamine system and to define its ability to control alcohol intake. These experiments revealed that central LEAP2 (i.e. into the third ventricle) prevented the ability of alcohol to cause locomotor stimulation in male mice, suppressed the memory of alcohol reward and attenuated the dopamine release in the nucleus accumbens caused by alcohol. Moreover, central LEAP2 reduced alcohol consumption in both male and female rats exposed to alcohol for 6 weeks before treatment. However, the serum levels of LEAP2 were similar between high- and low- alcohol-consuming (male) rats. Furthermore, central LEAP2 lowered the food intake in the alcohol-consuming male rats and reduced the body weight in the females. Collectively, the present study revealed that central LEAP2 mitigates alcohol-related responses in rodents, contributing to our understanding of the ghrelin pathway's role in alcohol effects.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"401"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366635","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":"Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.","authors":"Illana Gozes, Jason Blatt, Alexandra Lobyntseva","doi":"10.1038/s41398-024-03118-0","DOIUrl":"10.1038/s41398-024-03118-0","url":null,"abstract":"<p><strong>Background: </strong>The tauopathy inhibitor, davunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy. Extending these findings to prodromal Alzheimer's disease, we submitted a double-blind, placebo-controlled, 12 weeks/16 weeks follow-up, davunetide clinical trial results in amnestic mild cognitive impairment (ClinicalTrials.gov ID NCT00422981), to a sex-dependent analysis.</p><p><strong>Methods: </strong>One hundred forty-four individuals, separated into eight groups (1:2 placebo-and 2 doses, 5 mg davunetide/daily or 15 mg davunetide/twice-daily, with matching placebo intranasal volumes), were evaluated.</p><p><strong>Results: </strong>Significant dose-dependent cognitive increases were observed in men compared to women with a test of delayed (12 ss) visual matching to the sample. In a test of semantic working memory and attention (digit span), women showed a significant low-dose placebo effect, ensuing in a high dose significant davunetide improvement, over the matched placebo. Correlating anxiety with cognition showed sex-opposing results, with women depicting significant anxiety correlations with delayed matching to sample.</p><p><strong>Discussion: </strong>In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"412"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366606","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 involvement of K⁺ channels in depression and pharmacological effects of antidepressants on these channels.","authors":"Xian-Tao Li","doi":"10.1038/s41398-024-03069-6","DOIUrl":"10.1038/s41398-024-03069-6","url":null,"abstract":"<p><p>Depression is a common and complex psychiatric illness with multiple clinical symptoms, even leading to the disability and suicide. Owing to the partial understanding of the pathogenesis of depressive-like disorders, available pharmacotherapeutic strategies are developed mainly based on the \"monoamine hypothesis\", resulting in a limited effectiveness and a number of adverse effects in the clinical practice. The concept of multiple pathogenic factors be helpful for clarifying the etiology of depression and developing the antidepressants. It is well documented that K⁺ channels serve crucial roles in modulating the neuronal excitability and neurotransmitter release in the brain, and abnormality of these channels participated in the pathogenic process of diverse central nervous system (CNS) pathologies, such as seizure and Alzheimer's disease (AD). The clinical and preclinical evidence also delineates that the involvement of several types of K⁺ channels in depressive-like behaviors appear to be evident, suggesting these channels being one of the multiple factors in the etiology of this debilitating disorder. Emerging data manifest that diverse antidepressants impact distinct K⁺ channels, such as Kv, Kir and K_2P, meaning the functioning of these drug via a \"multi-target\" manner. On the other hand, the scenario of antidepressants impinging K⁺ channels could render an alternative interpretation for the pharmacological effectiveness and numerous side effects in clinical trials. Furthermore, these channels serve to be considered as a \"druggable target\" to develop novel therapeutic compound to antagonize this psychiatry.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"411"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366638","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":"Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology.","authors":"João Paulo Lima Santos, Amelia Versace, Manan Arora, Michele A Bertocci, Henry W Chase, Alex Skeba, Simona Graur, Lisa Bonar, Chiara Maffei, Anastasia Yendiki, Steven A Rasmussen, Suzanne N Haber, Mary L Phillips","doi":"10.1038/s41398-024-03101-9","DOIUrl":"10.1038/s41398-024-03101-9","url":null,"abstract":"<p><p>Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"410"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366610","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":"Nighttime-specific differential gene expression in suprachiasmatic nucleus and habenula is associated with resilience to chronic social stress.","authors":"Priyam Narain, Aleksa Petković, Marko Šušić, Salma Haniffa, Mariam Anwar, Marc Arnoux, Nizar Drou, Giuseppe Antonio-Saldi, Dipesh Chaudhury","doi":"10.1038/s41398-024-03100-w","DOIUrl":"10.1038/s41398-024-03100-w","url":null,"abstract":"<p><p>The molecular mechanisms that link stress and biological rhythms still remain unclear. The habenula (Hb) is a key brain region involved in regulating diverse types of emotion-related behaviours while the suprachiasmatic nucleus (SCN) is the body's central clock. To investigate the effects of chronic social stress on transcription patterns, we performed gene expression analysis in the Hb and SCN of stress-naïve and stress-exposed mice. Our analysis revealed a large number of differentially expressed genes and enrichment of synaptic and cell signalling pathways between resilient and stress-naïve mice at zeitgeber 16 (ZT16) in both the Hb and SCN. This transcriptomic signature was nighttime-specific and observed only in stress-resilient mice. In contrast, there were relatively few differences between the stress-susceptible and stress-naïve groups across time points. Our results reinforce the functional link between circadian gene expression patterns and differential responses to stress, thereby highlighting the importance of temporal expression patterns in homoeostatic stress responses.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"407"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366636","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 relationship between COMT, proline, and negative symptoms in clinical high risk and recent psychosis onset.","authors":"James D Clelland, Hannah Hesson, Krista Ramiah, Julia Anderson, Abraham Thengampallil, Ragy R Girgis, Catherine L Clelland","doi":"10.1038/s41398-024-03099-0","DOIUrl":"10.1038/s41398-024-03099-0","url":null,"abstract":"<p><p>Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase (COMT) Val¹⁵⁸Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total (n = 50, β = 0.066, adjusted p = 0.007) and global severity scores (n = 50, coefficient = 0.026, adjusted p = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores (n = 50, β-coefficient = 0.035, adjusted p = 0.044), although this result did not reach the Benjamini-Hochberg's threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = -0.005, adjusted p = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"409"},"PeriodicalIF":5.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366639","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}