{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T21:38:13Z","timestamp":1793655493986,"version":"4.5.1"},"reference-count":40,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Some observational studies have reported that sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors may have an impact on psychiatric disorders. This Mendelian randomization (MR) study aims to explore the causal relationship between SGLT2 inhibition and five types of psychiatric disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Genetic variants associated with the SLC5A2 gene and glycated hemoglobin were selected from the eQTLGen Consortium and Genotype-Tissue Expression datasets. Type 2 diabetes served as a positive control in the application of MR and colocalization analyses to investigate potential causal relationships between SGLT2 inhibition and depression, anxiety disorder, schizophrenia, obsessive-compulsive disorder, and bipolar affective disorder. The impact of glycated hemoglobin on psychiatric disorders was additionally analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SGLT2 inhibition was associated with an increased risk of anxiety disorder, obsessive-compulsive disorder, and bipolar affective disorder. The effect of SGLT2 inhibition on depression did not reach Bonferroni-corrected significance levels. No association was found between SGLT2 inhibition and schizophrenia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides genetic evidence supporting that SGLT2 inhibitors increase the risk of obsessive-compulsive disorder, anxiety disorder, and bipolar affective disorder.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/med-2025-1278","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T06:59:36Z","timestamp":1761548376000},"source":"Crossref","is-referenced-by-count":2,"title":["Association of SGLT2 inhibition with psychiatric disorders: A Mendelian randomization study"],"prefix":"10.1515","volume":"20","author":[{"given":"Le","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University , Changsha , Hunan , China"},{"name":"Institute of Aging and Age-related Disease Research, Central South University , Changsha , Hunan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University , Changsha , Hunan , China"},{"name":"Institute of Aging and Age-related Disease Research, Central South University , Changsha , Hunan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University , 139 Renmin Middle Road, Furong District , Changsha , Hunan , China"},{"name":"Institute of Aging and Age-related Disease Research, Central South University , Changsha , Hunan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkun","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University , 139 Renmin Middle Road, Furong District , Changsha , Hunan , China"},{"name":"Institute of Aging and Age-related Disease Research, Central South University , Changsha , Hunan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youshuo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Second Xiangya Hospital, Central South University , 139 Renmin Middle Road, Furong District , Changsha , Hunan , China"},{"name":"Institute of Aging and Age-related Disease Research, Central South University , Changsha , Hunan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2025,10,25]]},"reference":[{"key":"2025122201305408855_j_med-2025-1278_ref_001","doi-asserted-by":"crossref","unstructured":"van Sloten TT, Sedaghat S, Carnethon MR, Launer LJ, Stehouwer CDA. Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. Lancet Diabetes Endocrinol. 2020;8(4):325\u201336. 10.1016\/s2213-8587(19)30405-x.","DOI":"10.1016\/S2213-8587(19)30405-X"},{"key":"2025122201305408855_j_med-2025-1278_ref_002","doi-asserted-by":"crossref","unstructured":"Basiri R, Seidu B, Rudich M. Exploring the interrelationships between diabetes, nutrition, anxiety, and depression: implications for treatment and prevention strategies. Nutrients. 2023;15(19):4226. 10.3390\/nu15194226.","DOI":"10.3390\/nu15194226"},{"key":"2025122201305408855_j_med-2025-1278_ref_003","doi-asserted-by":"crossref","unstructured":"Suvisaari J, Kein\u00e4nen J, Eskelinen S, Mantere O. Diabetes and schizophrenia. Curr Diab Rep. 2016;16(2):16. 10.1007\/s11892-015-0704-4.","DOI":"10.1007\/s11892-015-0704-4"},{"key":"2025122201305408855_j_med-2025-1278_ref_004","doi-asserted-by":"crossref","unstructured":"Gorczynski P, Firth J, Stubbs B, Rosenbaum S, Vancampfort D. Are people with schizophrenia adherent to diabetes medication? A comparative meta-analysis. Psychiatry Res. 2017;250:17\u201324. 10.1016\/j.psychres.2017.01.049.","DOI":"10.1016\/j.psychres.2017.01.049"},{"key":"2025122201305408855_j_med-2025-1278_ref_005","doi-asserted-by":"crossref","unstructured":"Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021;398(10296):262\u201376. 10.1016\/s0140-6736(21)00536-5.","DOI":"10.1016\/S0140-6736(21)00536-5"},{"key":"2025122201305408855_j_med-2025-1278_ref_006","doi-asserted-by":"crossref","unstructured":"Cowie MR, Fisher M. SGLT2 inhibitors:mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761\u201372. 10.1038\/s41569-020-0406-8.","DOI":"10.1038\/s41569-020-0406-8"},{"key":"2025122201305408855_j_med-2025-1278_ref_007","doi-asserted-by":"crossref","unstructured":"Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400(10354):757\u201367. 10.1016\/s0140-6736(22)01429-5.","DOI":"10.1016\/S0140-6736(22)01429-5"},{"key":"2025122201305408855_j_med-2025-1278_ref_008","doi-asserted-by":"crossref","unstructured":"Bailey CJ, Day C, Bellary S. Renal protection with SGLT2 inhibitors: effects in acute and chronic kidney disease. Curr Diab Rep. 2022;22(1):39\u201352. 10.1007\/s11892-021-01442-z.","DOI":"10.1007\/s11892-021-01442-z"},{"key":"2025122201305408855_j_med-2025-1278_ref_009","doi-asserted-by":"crossref","unstructured":"Mui JV, Li L, Chou OHI, Azfar N, Lee A, Hui J, et al. Comparing sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors on new-onset depression: a propensity score-matched study in Hong Kong. Acta Diabetol. 2023;60(7):917\u201327. 10.1007\/s00592-023-02063-6.","DOI":"10.1007\/s00592-023-02063-6"},{"key":"2025122201305408855_j_med-2025-1278_ref_010","doi-asserted-by":"crossref","unstructured":"Wium-Andersen IK, Osler M, J\u00f8rgensen MB, Rungby J, Wium-Andersen MK. Diabetes, antidiabetic medications and risk of depression \u2013 a population-based cohort and nested case\u2013control study. Psychoneuroendocrinology. 2022;140:105715. 10.1016\/j.psyneuen.2022.105715.","DOI":"10.1016\/j.psyneuen.2022.105715"},{"key":"2025122201305408855_j_med-2025-1278_ref_011","doi-asserted-by":"crossref","unstructured":"Muhammad RN, Ahmed LA, Abdul Salam RM, Ahmed KA, Attia AS. Crosstalk among NLRP3 inflammasome, ET(B)R signaling, and miRNAs in stress-induced depression-like behavior: a modulatory role for SGLT2 inhibitors. Neurotherapeutics. 2021;18(4):2664\u201381. 10.1007\/s13311-021-01140-4.","DOI":"10.1007\/s13311-021-01140-4"},{"key":"2025122201305408855_j_med-2025-1278_ref_012","doi-asserted-by":"crossref","unstructured":"Larsson SC, Butterworth AS, Burgess S. Mendelian randomization for cardiovascular diseases: principles and applications. Eur Heart J. 2023;44(47):4913\u201324. 10.1093\/eurheartj\/ehad736.","DOI":"10.1093\/eurheartj\/ehad736"},{"key":"2025122201305408855_j_med-2025-1278_ref_013","doi-asserted-by":"crossref","unstructured":"Julian TH, Boddy S, Islam M, Kurz J, Whittaker KJ, Moll T, et al. A review of Mendelian randomization in amyotrophic lateral sclerosis. Brain. 2022;145(3):832\u201342. 10.1093\/brain\/awab420.","DOI":"10.1093\/brain\/awab420"},{"key":"2025122201305408855_j_med-2025-1278_ref_014","doi-asserted-by":"crossref","unstructured":"Pigeyre M, Sjaarda J, Chong M, Hess S, Bosch J, Yusuf S, et al. ACE and type 2 diabetes risk: a Mendelian randomization study. Diabetes Care. 2020;43(4):835\u201342. 10.2337\/dc19-1973.","DOI":"10.2337\/dc19-1973"},{"key":"2025122201305408855_j_med-2025-1278_ref_015","doi-asserted-by":"crossref","unstructured":"Li J, Yu Y, Sun Y, Yu B, Tan X, Wang B, et al. SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study. Cardiovasc Diabetol. 2023;22(1):278. 10.1186\/s12933-023-02019-8.","DOI":"10.1186\/s12933-023-02019-8"},{"key":"2025122201305408855_j_med-2025-1278_ref_016","unstructured":"Yarmolinsky J, Bouras E, Constantinescu A, Burrows K, Bull CJ, Vincent EE, et al. Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis. Diabetologia. 2023;66(8):1481\u2013500. 10.1007\/s00125-023-05925-4."},{"key":"2025122201305408855_j_med-2025-1278_ref_017","doi-asserted-by":"crossref","unstructured":"Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA. 2017;318(19):1925\u20136. 10.1001\/jama.2017.17219.","DOI":"10.1001\/jama.2017.17219"},{"key":"2025122201305408855_j_med-2025-1278_ref_018","doi-asserted-by":"crossref","unstructured":"Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA. 2021;326(16):1614\u201321. 10.1001\/jama.2021.18236.","DOI":"10.1001\/jama.2021.18236"},{"key":"2025122201305408855_j_med-2025-1278_ref_019","unstructured":"V\u00f5sa U, Claringbould A, Westra HJ, Bonder MJ, Deelen P, Zeng B, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021;53(9):1300\u201310. 10.1038\/s41588-021-00913-z."},{"key":"2025122201305408855_j_med-2025-1278_ref_020","unstructured":"GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318\u201330. 10.1126\/science.aaz1776."},{"key":"2025122201305408855_j_med-2025-1278_ref_021","unstructured":"Kurki MI, Karjalainen J, Palta P, Sipil\u00e4 TP, Kristiansson K, Donner KM, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613(7944):508\u201318. 10.1038\/s41586-022-05473-8."},{"key":"2025122201305408855_j_med-2025-1278_ref_022","doi-asserted-by":"crossref","unstructured":"Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2019;4:186. 10.12688\/wellcomeopenres.15555.3.","DOI":"10.12688\/wellcomeopenres.15555.1"},{"key":"2025122201305408855_j_med-2025-1278_ref_023","doi-asserted-by":"crossref","unstructured":"Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512\u201325. 10.1093\/ije\/dyv080.","DOI":"10.1093\/ije\/dyv080"},{"key":"2025122201305408855_j_med-2025-1278_ref_024","doi-asserted-by":"crossref","unstructured":"Zuber V, Grinberg NF, Gill D, Manipur I, Slob EAW, Patel A, et al. Combining evidence from Mendelian randomization and colocalization: review and comparison of approaches. Am J Hum Genet. 2022;109(5):767\u201382. 10.1016\/j.ajhg.2022.04.001.","DOI":"10.1016\/j.ajhg.2022.04.001"},{"key":"2025122201305408855_j_med-2025-1278_ref_025","unstructured":"Rasooly D, Peloso GM, Pereira AC, Dashti H, Giambartolomei C, Wheeler E, et al. Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure. Nat Commun. 2023;14(1):3826. 10.1038\/s41467-023-39253-3."},{"key":"2025122201305408855_j_med-2025-1278_ref_026","doi-asserted-by":"crossref","unstructured":"Chen S, Coronel R, Hollmann MW, Weber NC, Zuurbier CJ. Direct cardiac effects of SGLT2 inhibitors. Cardiovasc Diabetol. 2022;21(1):45. 10.1186\/s12933-022-01480-1.","DOI":"10.1186\/s12933-022-01480-1"},{"key":"2025122201305408855_j_med-2025-1278_ref_027","doi-asserted-by":"crossref","unstructured":"Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819\u201329. 10.1016\/s0140-6736(20)31824-9.","DOI":"10.1016\/S0140-6736(20)31824-9"},{"key":"2025122201305408855_j_med-2025-1278_ref_028","doi-asserted-by":"crossref","unstructured":"Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31\u20139. 10.1016\/s0140-6736(18)32590-x.","DOI":"10.1016\/S0140-6736(18)32590-X"},{"key":"2025122201305408855_j_med-2025-1278_ref_029","doi-asserted-by":"crossref","unstructured":"Giugliano D, Longo M, Scappaticcio L, Bellastella G, Maiorino MI, Esposito K. SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs. Cardiovasc Diabetol. 2021;20(1):236. 10.1186\/s12933-021-01430-3.","DOI":"10.1186\/s12933-021-01430-3"},{"key":"2025122201305408855_j_med-2025-1278_ref_030","doi-asserted-by":"crossref","unstructured":"Liebers DT, Ebina W, Iosifescu DV. Sodium-glucose cotransporter-2 inhibitors in depression. Harv Rev Psychiatry. 2023;31(4):214\u201321. 10.1097\/hrp.0000000000000374.","DOI":"10.1097\/HRP.0000000000000374"},{"key":"2025122201305408855_j_med-2025-1278_ref_031","doi-asserted-by":"crossref","unstructured":"Dong D, Liu X, Ma L, Hao YL, Zhang L, Song M, et al. Dapagliflozin inhibits the activity of lateral habenula to alleviate diabetes mellitus-induced depressive-like behavior. Exp Neurol. 2023;366:114448. 10.1016\/j.expneurol.2023.114448.","DOI":"10.1016\/j.expneurol.2023.114448"},{"key":"2025122201305408855_j_med-2025-1278_ref_032","doi-asserted-by":"crossref","unstructured":"Robbins TW, Vaghi MM, Banca P. Obsessive-compulsive disorder: puzzles and prospects. Neuron. 2019;102(1):27\u201347. 10.1016\/j.neuron.2019.01.046.","DOI":"10.1016\/j.neuron.2019.01.046"},{"key":"2025122201305408855_j_med-2025-1278_ref_033","doi-asserted-by":"crossref","unstructured":"Mahjani B, Bey K, Boberg J, Burton C. Genetics of obsessive-compulsive disorder. Psychol Med. 2021;51(13):2247\u201359. 10.1017\/s0033291721001744.","DOI":"10.1017\/S0033291721001744"},{"key":"2025122201305408855_j_med-2025-1278_ref_034","doi-asserted-by":"crossref","unstructured":"Stein DJ, Costa DLC, Lochner C, Miguel EC, Reddy YCJ, Shavitt RG, et al. Obsessive-compulsive disorder. Nat Rev Dis Primers. 2019;5(1):52. 10.1038\/s41572-019-0102-3.","DOI":"10.1038\/s41572-019-0102-3"},{"key":"2025122201305408855_j_med-2025-1278_ref_035","doi-asserted-by":"crossref","unstructured":"Scherrer JF, Salas J, Floyd JS, Farr SA, Morley JE, Dublin S. Metformin and sulfonylurea use and risk of incident dementia. Mayo Clin Proc. 2019;94(8):1444\u201356. 10.1016\/j.mayocp.2019.01.004.","DOI":"10.1016\/j.mayocp.2019.01.004"},{"key":"2025122201305408855_j_med-2025-1278_ref_036","doi-asserted-by":"crossref","unstructured":"Cernea S, Dima L, Correll CU, Manu P. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs. 2020;80(17):1763\u201381. 10.1007\/s40265-020-01393-x.","DOI":"10.1007\/s40265-020-01393-x"},{"key":"2025122201305408855_j_med-2025-1278_ref_037","doi-asserted-by":"crossref","unstructured":"Holmes MV, Richardson TG, Ference BA, Davies NM, Davey Smith G. Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development. Nat Rev Cardiol. 2021;18(6):435\u201353. 10.1038\/s41569-020-00493-1.","DOI":"10.1038\/s41569-020-00493-1"},{"key":"2025122201305408855_j_med-2025-1278_ref_038","doi-asserted-by":"crossref","unstructured":"Swanson SA, Tiemeier H, Ikram MA, Hern\u00e1n MA. Nature as a Trialist? Deconstructing the analogy between Mendelian randomization and randomized trials. Epidemiology. 2017;28(5):653\u20139. 10.1097\/ede.0000000000000699.","DOI":"10.1097\/EDE.0000000000000699"},{"key":"2025122201305408855_j_med-2025-1278_ref_039","doi-asserted-by":"crossref","unstructured":"Burgess S, Butterworth AS, Thompson JR. Beyond Mendelian randomization: how to interpret evidence of shared genetic predictors. J Clin Epidemiol. 2016;69:208\u201316. 10.1016\/j.jclinepi.2015.08.001.","DOI":"10.1016\/j.jclinepi.2015.08.001"},{"key":"2025122201305408855_j_med-2025-1278_ref_040","doi-asserted-by":"crossref","unstructured":"Luo S, Lam HS, Chan YH, Tang CSM, He B, Kwok MK, et al. Assessing the safety of lipid-modifying medications among Chinese adolescents: a drug\u2013target Mendelian randomization study. BMC Med. 2023;21(1):410. 10.1186\/s12916-023-03115-y.","DOI":"10.1186\/s12916-023-03115-y"}],"container-title":["Open Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1278\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1278\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T01:38:18Z","timestamp":1766367498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1278\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,6,9]]},"published-print":{"date-parts":[[2025,6,9]]}},"alternative-id":["10.1515\/med-2025-1278"],"URL":"https:\/\/doi.org\/10.1515\/med-2025-1278","relation":{},"ISSN":["2391-5463"],"issn-type":[{"value":"2391-5463","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,1]]},"article-number":"20251278"}}