Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression

Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression norihiro okada, Kenshiro Oshima, Akiko Maruko, Yoshinori Kobayashi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5823020/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract In response to a state of stress, the body attempts to maintain protein homeostasis through intron retention (IR). In other words, by examining which genes undergo IR under stress (i.e., IR genes), it is possible to analyze what type of stress the body is experiencing (Okada et al. 2024 Front.Psychiatry). Using this principle, we re-analyzed the RNA-seq data of non-responders and responders to ketamine, a drug with specific efficacy for depression, published by Cathomas et al. (2022), and examined IR genes to investigate what the substance of non-responders is. It was found that non-responders were individuals in a state of elevated viral infection. Several IR genes associated with viral infection were restored to a healthy state by ketamine regardless of whether an individual was a non-responder or a responder, so it is more reasonable to interpret that the non-responders are not individuals for whom ketamine does not work, but rather that the effects of ketamine do not catch up due to the extremely elevated inflammatory state of the non-responders. Furthermore, there is one transcriptomic outlier in the non-responders who shows an extreme increase in viral infection, but even if such an individual is excluded from the analysis, the above conclusions from the IR gene analysis remain essentially unchanged, whereas the DEG data were largely changed after this treatment. This further supports our previous claim that IR genes, but not DEGs, may be useful as markers of depression. This study is the first to describe the molecular basis of the difference between non-responders and responders. Biological sciences/Genetics/Gene expression Health sciences/Biomarkers/Diagnostic markers Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Additional Declarations Competing interest reported. NO, KO, and AM received a research grant from Tsumura & Co. Although Tsumura is a manufacturer of the Japanese herbal medicine, the company did not provide any medicines used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Supplementary Files TPsupplementaryFigures.pdf supplementaryTables.ver1.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 30 Apr, 2025 Reviews received at journal 30 Apr, 2025 Reviewers agreed at journal 10 Apr, 2025 Reviews received at journal 05 Mar, 2025 Reviewers agreed at journal 01 Mar, 2025 Reviewers agreed at journal 20 Feb, 2025 Reviewers invited by journal 18 Feb, 2025 Editor assigned by journal 09 Feb, 2025 Submission checks completed at journal 05 Feb, 2025 First submitted to journal 13 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5823020","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":401750985,"identity":"03fa5ea8-5275-4bf5-bacb-4acfe5590db5","order_by":0,"name":"norihiro okada","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYDACHgYGCRDNJsHYwMBQAWQxMzeQouUMSAsjkVrAJGMbiEVACz/P4Yc3fu6wyeeTbm778HFebTR/O1DLj4ptOLVI9rYZW/aeSbNskznYPHPmtuO5Mw4zNjD2nLmNU4vBeQYzCd62wwZsEonNzLzbjuU2ALUwM7bh08L+TfIvXMucY7nzCWo522MmjbCloSZ3AyEtkj1niq1l29LAWhhnHDuQuxGo5SA+v/DzpG+8+bbNxkB+Rvpjhg81dbnzzh8++OBHBW4t6OAwmDxAtHogqCNF8SgYBaNgFIwQAAABsleCnPtsuQAAAABJRU5ErkJggg==","orcid":"","institution":"Kitasato University","correspondingAuthor":true,"prefix":"","firstName":"norihiro","middleName":"","lastName":"okada","suffix":""},{"id":401750986,"identity":"a246444c-e756-4e03-8580-912c95d9f696","order_by":1,"name":"Kenshiro Oshima","email":"","orcid":"","institution":"Kitasato University","correspondingAuthor":false,"prefix":"","firstName":"Kenshiro","middleName":"","lastName":"Oshima","suffix":""},{"id":401750987,"identity":"25a29089-b2b2-4604-9539-aae686d3d8f2","order_by":2,"name":"Akiko Maruko","email":"","orcid":"","institution":"Kitasato University","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Maruko","suffix":""},{"id":401750988,"identity":"fc91f3dd-2195-4e43-85fa-a898cb1d11fd","order_by":3,"name":"Yoshinori Kobayashi","email":"","orcid":"","institution":"Kitasato University","correspondingAuthor":false,"prefix":"","firstName":"Yoshinori","middleName":"","lastName":"Kobayashi","suffix":""}],"badges":[],"createdAt":"2025-01-14 00:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5823020/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5823020/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75067037,"identity":"9db34fd9-94db-44dd-91b3-a121f192bc25","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1725024,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSample information and RNA-seq data analysis pipeline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Table with data information for each group. The number of reads used for mapping is shown as mean, minimum and maximum in each group. (B)(i) Scheme showing the analysis pipeline from downloaded raw FASTQ files of RNA-seq data used in this study. (ii) The pipeline described in the article by Cathomas et al [16].\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/99d5da09fa0fcf1269404ff1.jpeg"},{"id":75067047,"identity":"d94e7ed6-3f11-46de-82ff-45d1283d4ae8","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":631112,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDifferentially expressed genes (DEGs) analysis reveals differences between non-responders and responders.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A, B) DEGs analysis between non-responders (A) or responders (B) and CON (baseline). (i) Volcano plots of RNA expression comparisons are shown. The vertical axis shows -log10 \u003cem\u003eP\u003c/em\u003e-values and the horizontal axis shows log2 fold-change. Genes with significant changes are shown in red (up-regulation) and blue (down-regulation) (threshold: \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05 and fold-change \u0026gt;1.2). Symbols are shown for the top 10 genes with the lowest \u003cem\u003eP\u003c/em\u003e-values among the respective up- and down-regulated genes. (ii, iii) GO enrichment analysis using up-regulated (ii) and down-regulated (iii) genes. Horizontal axis indicates -log10 \u003cem\u003eP\u003c/em\u003e-values. Vertical axis indicates enriched GO term and number of genes corresponding to this term in parentheses. GO terms related to innate immunity are indicated in bold. (C) DEGs analysis between non-responders and responders (baseline), where the conditions and presentation of the analysis are the same as in (A,B).\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/fc95144a945c699ab2b4fd45.jpeg"},{"id":75067042,"identity":"5436a5c2-785b-40e0-a525-ce9fa9faaf31","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1360623,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eViral infection was detected in non-responders by using JR.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A,B) IR analysis between non-responders (A) or responders (B) and CON (baseline). (i) Scatter plots of IR ratio comparisons are shown. The vertical axis shows -log10 \u003cem\u003eP\u003c/em\u003e-values and the horizontal axis shows the difference in IR ratio (∆IR). Genes with significant changes are shown in red (IncIR genes) and blue (DecIR genes) (threshold: \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05 and absolute ∆IR \u0026gt; 0.05). Symbols for the top 10 genes with the lowest \u003cem\u003eP\u003c/em\u003e-values among the respective genes that were IncIR and DecIR genes are shown. (ii) GO and KEGG enrichment analysis performed by merging IncIR and DecIR genes. The horizontal axis indicates -log10 \u003cem\u003eP\u003c/em\u003e-values. Deep blue bars indicate GO terms and orange bars indicate KEGG pathway names. Vertical axis indicates enriched GO/KEGG term and number of genes corresponding to this term in parentheses. Bold indicates GO/KEGG terms related to innate immunity. (C, D) Venn diagram showing inflammation (i) and immunity-related genes (ii, iii) among IncIR/DecIR genes in the non-responders (C) and responders (D). Comparison with gene sets containing the term \"GO:0006954 inflammatory response\" (508 genes) (i), the term \"GO:0045087 innate immune response\" (698 genes) (ii) and the term \"GO:0002250 adaptive immune response\" (764 genes) (iii) were performed.\u003c/p\u003e","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/c7a25be42829086f90eed312.jpeg"},{"id":75067040,"identity":"221d32be-cfe3-4a28-91e6-0853ceb7f32c","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2028362,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDEGs and JR genes recovered by ketamine \u003c/strong\u003eadministration\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A, B) Detection of recovered DEG genes by ketamine by analyses of overlapping. Genes in bold indicates those related to innate immunity. In each of (A) and (B), the left and right panels show the cases of non-responders and responders, respectively. (A) Venn diagram comparing genes whose RNA expression is up-regulated in TRD patients and down-regulated by ketamine administration (reverse V-shape). (B) Venn diagram comparing genes whose RNA expression is down-regulated in TRD patients and up-regulated by ketamine administration (V-shape). (C, D) Box and whisker plots of relative IR ratio after ketamine administration. (C) Profiles of non-responders of 65 IncIR loci (i) and 145 DecIR loci (ii). (D) Profiles of responders of 45 IncIR loci (i) and 98 DecIR loci (ii). (E, F) Detection of recovered IR genes by ketamine by analyses of overlapping. In each of (E) and (F), the left and right panels show the cases of non-responders and responders, respectively. (E) Venn diagrams comparing genes whose IR ratio is increased (IncIR) loci in TRD patients and decreased (DecIR) loci by ketamine administration (reverse V-shape). (F) Venn diagrams comparing genes whose IR ratio is decreased (DecIR) loci in TRD patients and increased (IncIR) loci by ketamine administration (V-shape). (G) Heatmaps showing recovery of IR in individuals of non-responders (i) and responders (ii). Relative IR ratios are indicated by z-scores. (H) GO enrichment analysis of recovery IR genes. Horizontal axis indicates -log10 \u003cem\u003eP\u003c/em\u003e-values. Dark blue bars are GO terms with \u003cem\u003eP\u003c/em\u003e-values \u0026lt; 0.05, light blue bars are those with no significant difference. GO in bold are related to innate immunity.\u003c/p\u003e","description":"","filename":"Figure4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/f58c0d61b0c899bc3a7cad22.jpeg"},{"id":75067043,"identity":"72152263-73b1-4456-b453-1e5356717cc9","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2015469,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eNon-responders and responders have different profiles of protein-protein interactions in the DEGs and JR genes.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Interaction of protein-coding IR genes against the gene set of the term \"GO:0006954 inflammatory response\" (505 genes). Networks were generated for interactions with a confidence score of 0.4 in the full STRING network using the STRING database. (Upper) Network of 43 IncIR and 93 DecIR protein-coding and innate immunity-related genes in the non-responders. (Lower) Network of 28 IncIR, 67 DecIR and 1 mixed protein-coding and innate immunity-related genes in the responders. (B) Table showing the genes of the non-responders (left) and the responders (right) ranked by the number of interactions (links). (C)(i) Bar graph showing the mean number of interactions in each group. Student t-test was used to compare significant differences. (ii) Bar chart showing the total number of interactions for each group. (D) Interaction networks focused on innate immunity-related genes in non-responders (i) and responders (ii). Large circles and squares indicate IR genes, in which red and blue show IncIR and DecIR genes, respectively. Small circles and squares indicate DEGs, in which red and blue show un-regulated and down-regulated DEGs, respectively. Squares indicate genes whose IR or expression was recovered after ketamine administration, and circles indicate unrecovered genes. Genes with red and blue borders indicate up-regulated genes and down-regulated genes, respectively. EEF1A1(i), NLRC5(i), LSM7(ii), CARD9(ii) and ITIH4(ii) in the red border were up-regulated between CON and PRE. (E) Bar graph showing the recovery of IR ratio or expression at the focused gene in the non-responders (i) and responders (ii). Error bars indicate standard deviation. Asterisks indicate \u003cem\u003eP\u003c/em\u003e-values by likelihood test (*: \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.05, **: \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.01, ***: \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"Figure5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/db278b48bd404e55b4563e87.jpeg"},{"id":75067044,"identity":"ab77fb07-2afd-49db-aeba-405e6390b3ef","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"jpeg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2016098,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExcluding outliers does not change the JR results.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Heatmap of all examined individuals using 352 genes that were defined as those with high expression variability and coefficient of variation (CV) values greater than 1. CV values were calculated by dividing the standard deviation by the mean expression. On the left, the 47 gene symbols that had a z-score \u0026gt;3 for both PRE and POST for non-responder_PB100 are listed. (B) GO enrichment analysis using 47 genes highly expressed in the outlier. Bold indicates GO terms related to innate immunity. Horizontal axis indicates -log10 \u003cem\u003eP\u003c/em\u003e-values. Vertical axis indicates enriched GO term and number of genes corresponding to that term in parentheses. (C) Venn diagram comparing DEGs or IR genes before and after excluding the outlier in the non-responders. (i) Analyses of DEGs remaining after exclusion of the outlier that were up-regulated (right) and down-regulated (left) genes. (ii) Analyses of DEGs remaining after exclusion of the outlier that were increased in IR (right) and decreased in IR (left) genes. (D) GO enrichment analysis using up-regulated (i) and down-regulated (ii) genes in non-responders after exclusion of the outlier. (E) GO and KEGG enrichment analysis performed by merging IncIR and DecIR genes in non-responders after exclusion of the outlier. Horizontal axis indicates -log10 \u003cem\u003eP\u003c/em\u003e-values. Deep blue bars indicate GO terms and orange bars indicate KEGG pathway names. Vertical axis indicates enriched GO/KEGG term and number of genes corresponding to this term in parentheses. Bold indicates GO/KEGG terms related to innate immunity. (F) Venn diagram showing inflammation- or innate immunity-related genes among the IncIR/DecIR genes in the non-responders, excluding the outlier. (i) Comparison with gene sets containing the term \"GO:0006954 inflammatory response\" (508 genes). (ii) Comparison with gene sets containing the term \"GO:0045087 innate immune response\" (698 genes). (iii) Comparison with gene sets containing the term \"GO:0002250 adaptive immune response\" (764 genes).\u003c/p\u003e","description":"","filename":"Figure6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/5ace7a7338ce71341112213b.jpeg"},{"id":75067917,"identity":"b23710ee-317a-4015-bd42-254d32a84304","added_by":"auto","created_at":"2025-01-30 06:14:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10374186,"visible":true,"origin":"","legend":"","description":"","filename":"AnalysisofTRDbyIRfinal2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1_covered_c42eba78-0220-45d8-847d-de99209e03fd.pdf"},{"id":75067036,"identity":"fe7cf274-1be1-497e-9864-4ea6a993e8e6","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1719956,"visible":true,"origin":"","legend":"","description":"","filename":"TPsupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/abb771000c43365b17434d01.pdf"},{"id":75067038,"identity":"dd06d216-eebe-4557-b751-5648060bd93c","added_by":"auto","created_at":"2025-01-30 05:58:42","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":343169,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryTables.ver1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5823020/v1/a0e62cd54f736d972bd2aa17.xlsx"}],"financialInterests":"Competing interest reported. NO, KO, and AM received a research grant from Tsumura \u0026 Co. Although Tsumura is a manufacturer of the Japanese herbal\nmedicine, the company did not provide any medicines used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.","formattedTitle":"Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-mental-health-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjmentalhealth","sideBox":"Learn more about [npj Mental Health Research](https://www.nature.com/npjmentalhealth/)","snPcode":"44184","submissionUrl":"https://mts-npjmentalhealth.nature.com/cgi-bin/main.p...","title":"npj Mental Health Research","twitterHandle":"@npjmentalhealth\n","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"npj","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5823020/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5823020/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"In response to a state of stress, the body attempts to maintain protein homeostasis through intron retention (IR). In other words, by examining which genes undergo IR under stress (i.e., IR genes), it is possible to analyze what type of stress the body is experiencing (Okada et al. 2024 Front.Psychiatry). Using this principle, we re-analyzed the RNA-seq data of non-responders and responders to ketamine, a drug with specific efficacy for depression, published by Cathomas et al. (2022), and examined IR genes to investigate what the substance of non-responders is. It was found that non-responders were individuals in a state of elevated viral infection. Several IR genes associated with viral infection were restored to a healthy state by ketamine regardless of whether an individual was a non-responder or a responder, so it is more reasonable to interpret that the non-responders are not individuals for whom ketamine does not work, but rather that the effects of ketamine do not catch up due to the extremely elevated inflammatory state of the non-responders. Furthermore, there is one transcriptomic outlier in the non-responders who shows an extreme increase in viral infection, but even if such an individual is excluded from the analysis, the above conclusions from the IR gene analysis remain essentially unchanged, whereas the DEG data were largely changed after this treatment. This further supports our previous claim that IR genes, but not DEGs, may be useful as markers of depression. This study is the first to describe the molecular basis of the difference between non-responders and responders.","manuscriptTitle":"Intron retention, a novel method for evaluating the response to ketamine in patients with treatment-resistant depression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-30 05:58:37","doi":"10.21203/rs.3.rs-5823020/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-30T13:16:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-30T13:08:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298041515559154734192838031316288679244","date":"2025-04-10T22:47:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-06T02:39:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"28477501988806860674564494550330364520","date":"2025-03-01T12:54:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"322737134500516237360548474745666227932","date":"2025-02-21T02:52:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-18T08:45:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-09T20:27:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-05T08:23:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Mental Health Research","date":"2025-01-14T00:32:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-mental-health-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjmentalhealth","sideBox":"Learn more about [npj Mental Health Research](https://www.nature.com/npjmentalhealth/)","snPcode":"44184","submissionUrl":"https://mts-npjmentalhealth.nature.com/cgi-bin/main.p...","title":"npj Mental Health Research","twitterHandle":"@npjmentalhealth\n","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"npj","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fde9dc89-6b30-4488-8b0b-77a142949fd9","owner":[],"postedDate":"January 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":42817646,"name":"Biological sciences/Genetics/Gene expression"},{"id":42817647,"name":"Health sciences/Biomarkers/Diagnostic markers"}],"tags":[],"updatedAt":"2025-09-01T22:23:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-30 05:58:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5823020","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5823020","identity":"rs-5823020","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}