{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T19:17:40Z","timestamp":1769887060418,"version":"3.49.0"},"reference-count":84,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023652","name":"University of Rijeka, Croatia","doi-asserted-by":"crossref","award":["uniri-biomed-18-251"],"award-info":[{"award-number":["uniri-biomed-18-251"]}],"id":[{"id":"10.13039\/501100023652","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023652","name":"University of Rijeka, Croatia","doi-asserted-by":"crossref","award":["uniri-biomed-18-230"],"award-info":[{"award-number":["uniri-biomed-18-230"]}],"id":[{"id":"10.13039\/501100023652","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023652","name":"University of Rijeka, Croatia","doi-asserted-by":"crossref","award":["uniri-iskusni-biomed-23-152"],"award-info":[{"award-number":["uniri-iskusni-biomed-23-152"]}],"id":[{"id":"10.13039\/501100023652","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We investigated whether antipsychotic treatment response was influenced by the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR), and A66G of methyltetrahydrofolate\u2013homocysteine methyltransferase reductase (MTRR)\u2014genes central to folate and homocysteine metabolism and methylation, pathways often altered in schizophrenia patients. To our knowledge, no study has examined associations of C677T and A1298C with changes in schizophrenia symptom severity after antipsychotic treatment, while studies on metabolic outcomes remain sparse and inconsistent. The MTRR A66G has been assessed only once for metabolic parameters\u2014not symptom severity\u2014and sex-stratified analyses are lacking for all polymorphisms. A total of 186 antipsychotic-na\u00efve first-episode or nonadherent chronic psychosis patients and 242 controls were genotyped using PCR-RFLP. Clinical assessments\u2014including Positive and Negative Syndrome Scale (PANSS) scores, PANSS factor scores, and metabolic parameters (fasting plasma lipids and glucose levels, and body mass index)\u2014were conducted at baseline and after 8 weeks. Genotype and allele frequencies did not differ between patients and controls. Significant associations emerged only for symptom changes, specifically within PANSS factor domains, in a sex-dependent manner. Female MTHFR 1298-A allele carriers (AA and AC) showed greater improvement in PANSS negative factor scores, whereas male MTRR 66-G allele carriers (GG and AG) showed reduced improvement in PANSS cognitive factor scores. Effect sizes were strong to very strong, with relatively modest contributions. MTHFR A1298C and MTRR A66G have sex-dependent impacts on symptomatic improvement\u2014but not metabolic outcomes\u2014after antipsychotic treatment. Accordingly, folate\u2013homocysteine genetic markers and sex-specific factors can guide the development of personalized antipsychotic treatment approaches.<\/jats:p>","DOI":"10.3390\/ijms27031348","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T12:49:07Z","timestamp":1769690947000},"page":"1348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MTHFR and MTRR Polymorphisms Predict Sex-Dependent Psychotic Symptom Improvements, Not Metabolic Changes"],"prefix":"10.3390","volume":"27","author":[{"given":"Sergej","family":"Nadalin","sequence":"first","affiliation":[{"name":"Department of Psychiatry, General Hospital \u201cDr. Josip Ben\u010devi\u0107\u201d, 35000 Slavonski Brod, Croatia"},{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Majdand\u017ei\u0107","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Reanimatology and Intensive Care Medicine, General Hospital \u201cDr. Josip Ben\u010devi\u0107\u201d, 35000 Slavonski Brod, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6365-5686","authenticated-orcid":false,"given":"Jadranka","family":"Vranekovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Medical Biology and Genetics, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-6411","authenticated-orcid":false,"given":"Vjekoslav","family":"Peitl","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"},{"name":"Department of Psychiatry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-5890","authenticated-orcid":false,"given":"Maja","family":"Vilibi\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"},{"name":"Department of Psychiatry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ante","family":"Sili\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"},{"name":"Department of Psychiatry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-7240","authenticated-orcid":false,"given":"Dalibor","family":"Karlovi\u0107","sequence":"additional","affiliation":[{"name":"School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia"},{"name":"Department of Psychiatry, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Saha, S., Chant, D., Welham, J., and McGrath, J. (2005). A systematic review of the prevalence of schizophrenia. PLoS Med., 2.","DOI":"10.1371\/journal.pmed.0020141"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12991-025-00557-x","article-title":"Epigenetics factors in schizophrenia: Future directions for etiologic and therapeutic study approaches","volume":"24","author":"Yang","year":"2025","journal-title":"Ann. Gen. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1080\/1028415X.2024.2436822","article-title":"Is There a Causal Link between Folate Status and Schizophrenia? Evidence from Genetic Association Studies","volume":"28","author":"Yoo","year":"2025","journal-title":"Nutr. Neurosci."},{"key":"ref_4","first-page":"1821","article-title":"Schizophrenia: A Review","volume":"75","author":"Schultz","year":"2007","journal-title":"Am. Fam. Physician"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1038\/s41380-024-02749-5","article-title":"Schizophrenia is Associated with Altered DNA Methylation Variance","volume":"30","author":"Kiltschewskij","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fan, N., Zhao, W., Yun, Y., Bai, L., An, H., Zhang, Q., Yan, J., Fan, F., Han, X., and Yang, F. (2024). Homocysteine Levels in First-Episode Patients with Psychiatric Disorders. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1380900"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Shih, Y.L., Shih, C.C., Huang, T.C., and Chen, J.Y. (2023). The Relationship between Elevated Homocysteine and Metabolic Syndrome in a Community-Dwelling Middle-Aged and Elderly Population in Taiwan. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020378"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ulloque-Badaracco, J.R., Hernandez-Bustamante, E.A., Alarcon-Braga, E.A., Al-Kassab-C\u00f3rdova, A., Cabrera-Guzm\u00e1n, J.C., Herrera-A\u00f1azco, P., and Benites-Zapata, V.A. (2023). Vitamin B12, Folate, and Homocysteine in Metabolic Syndrome: A Systematic Review and Meta-Analysis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1221259"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"McCaddon, A., and Miller, J.W. (2023). Homocysteine\u2014A Retrospective and Prospective Appraisal. Front. Nutr., 10.","DOI":"10.3389\/fnut.2023.1179807"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107253","DOI":"10.1016\/j.jbc.2024.107253","article-title":"Homocysteine-Induced Sustained GluN2A NMDA Receptor Stimulation Leads to Mitochondrial ROS Generation and Neurotoxicity","volume":"300","author":"Deep","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Younesian, S., Yousefi, A.M., Momeny, M., Ghaffari, S.H., and Bashash, D. (2022). The DNA Methylation in Neurological Diseases. Cells, 11.","DOI":"10.3390\/cells11213439"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13098-019-0484-0","article-title":"Hyperhomocysteinemia is an independent risk factor of atherosclerosis in patients with metabolic syndrome","volume":"11","author":"Piazzolla","year":"2019","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Jones, A.C., Ament, Z., Patki, A., Chaudhary, N.S., Srinivasasainagendra, V., Kijpaisalratana, N., Absher, D.M., Tiwari, H.K., Arnett, D.K., and Kimberly, W.T. (2023). Metabolite profiles and DNA methylation in metabolic syndrome: A two-sample, bidirectional Mendelian randomization. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1184661"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s12933-025-02800-x","article-title":"Epigenetic Crossroads in Metabolic and Cardiovascular Health: The Role of DNA Methylation in Type 2 Diabetes and Cardiovascular Diseases","volume":"24","author":"Kaimala","year":"2025","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1007\/s00228-014-1762-2","article-title":"Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients","volume":"70","author":"Misiak","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.neulet.2017.04.025","article-title":"Effect of Risperidone on Serum Homocysteine Levels in First-Episode, Drug-Na\u00efve Patients with Schizophrenia","volume":"650","author":"Fan","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kinoshita, M., Numata, S., Tajima, A., Yamamori, H., Yasuda, Y., Fujimoto, M., Watanabe, S., Umehara, H., Shimodera, S., and Nakazawa, T. (2017). Effect of Clozapine on DNA Methylation in Peripheral Leukocytes from Patients with Treatment-Resistant Schizophrenia. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030632"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/s41380-024-02735-x","article-title":"DNA Methylation and Histone Modifications Associated with Antipsychotic Treatment: A Systematic Review","volume":"30","author":"Marques","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ajp.2012.03.002","article-title":"Association between MTHFR C677T and A1298C, and MTRR A66G Polymorphisms and Susceptibility to Schizophrenia in a Syrian Study Cohort","volume":"5","author":"Lajin","year":"2012","journal-title":"Asian J. Psychiatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e21962","DOI":"10.1097\/MD.0000000000021962","article-title":"Association between Gene Polymorphism of Folate Metabolism and Recurrent Spontaneous Abortion in Asia: A Meta-Analysis","volume":"99","author":"Zhao","year":"2020","journal-title":"Medicine"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zarembska, E., \u015alusarczyk, K., and Wrzosek, M. (2023). The Implication of a Polymorphism in the Methylenetetrahydrofolate Reductase Gene in Homocysteine Metabolism and Related Civilisation Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010193"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"437","DOI":"10.4103\/ijmr.IJMR_745_14","article-title":"Methylenetetrahydrofolate Reductase A1298C Genetic Variant & Risk of Schizophrenia: A Meta-Analysis","volume":"145","author":"Rai","year":"2017","journal-title":"Indian J. Med. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, Y.X., Yang, L.P., Gai, C., Cheng, C.C., Guo, Z.Y., Sun, H.M., and Hu, D. (2022). Association between Variants of MTHFR Genes and Psychiatric Disorders: A Meta-Analysis. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.976428"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.schres.2007.01.003","article-title":"Effects of the Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism on Executive Function in Schizophrenia","volume":"92","author":"Roffman","year":"2007","journal-title":"Schizophr. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.schres.2007.09.030","article-title":"Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C\/T and 1298A\/C variants","volume":"98","author":"Ellingrod","year":"2008","journal-title":"Schizophr. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.biopsych.2006.12.017","article-title":"Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia","volume":"63","author":"Roffman","year":"2008","journal-title":"Biol. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.schres.2010.05.030","article-title":"MTHFR and Risk of Metabolic Syndrome in Patients with Schizophrenia","volume":"121","author":"Rutten","year":"2010","journal-title":"Schizophr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1097\/JCP.0b013e3182485888","article-title":"Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: The role of folate pharmacogenetics","volume":"32","author":"Ellingrod","year":"2012","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.bbr.2012.12.061","article-title":"Association of MTHFR C677T polymorphism with schizophrenia and its effect on episodic memory and gray matter density in patients","volume":"243","author":"Zhang","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2217\/pgs.13.220","article-title":"Association of FTO, LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics","volume":"15","author":"Roffeei","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10290","DOI":"10.18632\/aging.103248","article-title":"Interactive effect of MTHFR C677T polymorphism and sex on symptoms and cognitive functions in Chinese patients with chronic schizophrenia","volume":"12","author":"Gao","year":"2020","journal-title":"Aging"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, C.H., Chen, P.Y., Chen, C.Y.A., Chiu, C.C., Lu, M.L., Huang, M.C., Lin, Y.K., and Chen, Y.H. (2021). Associations of Genetic Variants of Methylenetetrahydrofolate Reductase and Serum Folate Levels with Metabolic Parameters in Patients with Schizophrenia. Int. J. Environ. Res. Public. Health, 18.","DOI":"10.3390\/ijerph182111333"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1097\/YIC.0b013e32833bc60d","article-title":"MTHFR genotype and differential evolution of metabolic parameters after initiation of a second-generation antipsychotic: An observational study","volume":"25","author":"Moons","year":"2010","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jpsychires.2014.03.012","article-title":"Methylenetetrahydrofolate Reductase Gene Variants and Antipsychotic-Induced Weight Gain and Metabolic Disturbances","volume":"54","author":"Kao","year":"2014","journal-title":"J. Psychiatr. Res."},{"key":"ref_35","first-page":"207","article-title":"Genetic Variation in One-Carbon Metabolism and Changes in Metabolic Parameters in First-Episode Schizophrenia Patients","volume":"20","author":"Misiak","year":"2017","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1017\/S1461145713001375","article-title":"Methylenetetrahydrofolate Reductase (MTHFR) 677C\/T Polymorphism Is Associated with Antipsychotic-Induced Weight Gain in First-Episode Schizophrenia","volume":"17","author":"Srisawat","year":"2014","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Su, Y., Yan, H., Guo, L., Lu, T., Zhang, D., and Yue, W. (2021). Association of MTHFR C677T Polymorphism with Antipsychotic-Induced Change of Weight and Metabolism Index. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.673715"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"114997","DOI":"10.1016\/j.psychres.2022.114997","article-title":"Gender Differences in the Response to Antipsychotic Medication in Patients with Schizophrenia: An Individual Patient Data Meta-Analysis of Placebo-Controlled Studies","volume":"320","author":"Storosum","year":"2023","journal-title":"Psychiatry Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00406-023-01644-4","article-title":"Gender Differences in Clinical and Biochemical Parameters among Patients Hospitalized for Schizophrenia: Towards Precision Medicine","volume":"274","author":"Esposito","year":"2024","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Nadalin, S., Devi\u0107 Pavli\u0107, S., Peitl, V., Karlovi\u0107, D., Zatkovi\u0107, L., Risti\u0107, S., Bureti\u0107-Tomljanovi\u0107, A., and Jakovac, H. (2022). Association between Insertion-Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Treatment Response to Antipsychotic Medications: A Study of Antipsychotic-Na\u00efve First-Episode Psychosis Patients and Nonadherent Chronic Psychosis Patients. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202209.0426.v1"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102578","DOI":"10.1016\/j.plefa.2023.102578","article-title":"Association between PLA2 Gene Polymorphisms and Treatment Response to Antipsychotic Medications: A Study of Antipsychotic-Na\u00efve First-Episode Psychosis Patients and Nonadherent Chronic Psychosis Patients","volume":"194","author":"Nadalin","year":"2023","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1007\/s00508-008-1065-7","article-title":"Differences in Risk Factors for Coronary Heart Disease in Patients from Continental and Mediterranean Regions of Croatia","volume":"120","author":"Bergovec","year":"2008","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.5671\/ca.2012361s.201","article-title":"Paving the Way for Personalised Behaviourally Based Prevention of Obesity: Systematic Search of the Literature","volume":"36","author":"Fister","year":"2012","journal-title":"Coll. Antropol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113","DOI":"10.5671\/ca.2012361s.113","article-title":"Obesity\u2014New Threat to Croatian Longevity","volume":"36","author":"Uhernik","year":"2012","journal-title":"Coll. Antropol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wu, Y., Li, D., and Vermund, S.H. (2024). Advantages and Limitations of the Body Mass Index (BMI) to Assess Adult Obesity. Int. J. Environ. Res. Public Health, 21.","DOI":"10.3390\/ijerph21060757"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yang, B., Liu, Y., Li, Y., Fan, S., Zhi, X., Lu, X., Wang, D., Zheng, Q., Wang, Y., and Wang, Y. (2013). Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: Findings from 15,357 adults of Han nationality. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057917"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wang, X., Fu, J., Li, Q., and Zeng, D. (2016). Geographical and ethnic distributions of the MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in Chinese populations: A meta-analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152414"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S2215-0366(19)30416-X","article-title":"Comparative Effects of 18 Antipsychotics on Metabolic Function in Patients with Schizophrenia: A Systematic Review and Network Meta-Analysis","volume":"7","author":"Pillinger","year":"2020","journal-title":"Lancet Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1002\/wps.21036","article-title":"Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: A network meta-analysis of randomized controlled trials","volume":"22","author":"Burschinski","year":"2023","journal-title":"World Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1093\/ijnp\/pyad029","article-title":"Weight gain and metabolic changes in patients with first-episode psychosis or early-phase schizophrenia treated with olanzapine: A meta-analysis","volume":"26","author":"Correll","year":"2023","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1192\/bjo.2022.619","article-title":"Association between antipsychotic medication and clinically relevant weight change: Meta-analysis","volume":"9","author":"Campforts","year":"2023","journal-title":"BJPsych Open"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1086\/301825","article-title":"A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural tube defects?","volume":"62","author":"Stevens","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13378","DOI":"10.1021\/bi020536s","article-title":"Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase","volume":"41","author":"Olteanu","year":"2002","journal-title":"Biochemistry"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Moretti, R., and Caruso, P. (2019). The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20010231"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A Candidate Genetic Risk Factor for Vascular Disease: A Common Mutation in Methylenetetrahydrofolate Reductase","volume":"10","author":"Frosst","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2486165","DOI":"10.1080\/03014460.2025.2486165","article-title":"Relationship between MTHFR, MTRR Gene Polymorphisms and H-Type Hypertension: A Systematic Review and Meta-Analysis","volume":"52","author":"Gao","year":"2025","journal-title":"Ann. Hum. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"138","DOI":"10.17305\/bb.2023.9260","article-title":"Association of MTHFR Polymorphism, Folic Acid and Vitamin B12 with Serum Homocysteine Levels in Pregnant Women","volume":"24","author":"Mandrapa","year":"2024","journal-title":"Biomol. Biomed."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13293-015-0029-7","article-title":"Sex Differences of Leukocyte DNA Methylation Adjusted for Estimated Cellular Proportions","volume":"6","author":"Inoshita","year":"2015","journal-title":"Biol. Sex Differ."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0008-6363(01)00462-X","article-title":"Estrogen and homocysteine","volume":"53","author":"Dimitrova","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"225","DOI":"10.4172\/2157-7609.1000225","article-title":"Epigenome-Wide Association (DNA Methylation) Study of Sex Differences in Normal Human Kidney","volume":"8","author":"Joseph","year":"2017","journal-title":"J. Drug Metab. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Niu, X.N., Wen, H., Sun, N., Yang, Y., Du, S.H., Xie, R., Zhang, Y.N., Li, Y., and Hong, X.Q. (2022). Estradiol and Hyperhomocysteinemia Are Linked Predominantly Through Part Renal Function Indicators. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.817579"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1093\/hmg\/ddt516","article-title":"Sex-Biased Methylome and Transcriptome in Human Prefrontal Cortex","volume":"23","author":"Xu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"249","DOI":"10.5812\/ircmj.9690","article-title":"Serum Level of Homocysteine, Folate and Vitamin B12 in Epileptic Patients under Carbamazepine and Sodium Valproate Treatment: A Systematic Review and Meta-Analysis","volume":"15","author":"Gorjipour","year":"2013","journal-title":"Iran. Red Crescent Med. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e004936","DOI":"10.1136\/bmjopen-2014-004936","article-title":"Increased Homocysteine Levels in Valproate-Treated Patients with Epilepsy: A Meta-Analysis","volume":"4","author":"Ni","year":"2014","journal-title":"BMJ Open"},{"key":"ref_65","first-page":"76","article-title":"Mood Stabilizers and the Influence on Global Leukocyte DNA Methylation in Bipolar Disorder","volume":"1","author":"Backlund","year":"2015","journal-title":"Mol. Neuropsychiatry"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2217\/epi.15.98","article-title":"DNA Methylation Signatures of Mood Stabilizers and Antipsychotics in Bipolar Disorder","volume":"8","author":"Houtepen","year":"2016","journal-title":"Epigenomics"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Webb, L.M., Phillips, K.E., Ho, M.C., Veldic, M., and Blacker, C.J. (2020). The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030826"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.2217\/epi-2022-0246","article-title":"Evaluation of DNA Methylation in BDNF, SLC6A4, NR3C1 and FKBP5 before and after Treatment with Selective Serotonin Reuptake Inhibitor in Major Depressive Disorder","volume":"14","author":"Mohammadi","year":"2022","journal-title":"Epigenomics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"102604","DOI":"10.1016\/j.plefa.2023.102604","article-title":"An association between PPAR\u03b1-L162V polymorphism and increased plasma LDL cholesterol levels after risperidone treatment","volume":"200","author":"Nadalin","year":"2024","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"102665","DOI":"10.1016\/j.plefa.2025.102665","article-title":"Association between the COX-2 rs689466 polymorphism and antipsychotic treatment: Impact on HDL cholesterol changes in clozapine-treated psychosis patients","volume":"204","author":"Nadalin","year":"2025","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Publishing. [5th ed.].","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/schbul\/13.2.261","article-title":"The positive and negative syndrome scale (PANSS) for schizophrenia","volume":"13","author":"Kay","year":"1987","journal-title":"Schizophr. Bull."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.schres.2012.01.031","article-title":"Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia","volume":"137","author":"Wallwork","year":"2012","journal-title":"Schizophr. Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Jiang, J., See, Y.M., Subramaniam, M., and Lee, J. (2013). Investigation of cigarette smoking among male schizophrenia patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071343"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.comppsych.2014.11.024","article-title":"Assessment of cigarette smoking status with respect to symptomatic manifestation in first-episode schizophrenia patients","volume":"58","author":"Misiak","year":"2015","journal-title":"Compr. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/s12291-021-00982-1","article-title":"Association of MTHFR C677T (rs1801133) and A1298C (rs1801131) Polymorphisms with Serum Homocysteine, Folate and Vitamin B12 in Patients with Young Coronary Artery Disease","volume":"37","author":"Shivkar","year":"2022","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Wang, Y., Du, M., Vallis, J., Shariati, M., Parfrey, P.S., Mclaughlin, J.R., Wang, P.P., and Zhu, Y. (2022). The Roles of MTRR and MTHFR Gene Polymorphisms in Colorectal Cancer Survival. Nutrients, 14.","DOI":"10.3390\/nu14214594"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0021-9150(02)00204-6","article-title":"Effects of Polymorphisms of Methionine Synthase and Methionine Synthase Reductase on Total Plasma Homocysteine in the NHLBI Family Heart Study","volume":"166","author":"Jacques","year":"2003","journal-title":"Atherosclerosis"},{"key":"ref_79","first-page":"1083","article-title":"Folate Gene Polymorphisms and the Risk of Down Syndrome Pregnancies in Young Italian Women","volume":"140","author":"Marini","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_80","first-page":"12","article-title":"Methyltetrahydrofolate-homocysteine methyltransferase reductase gene and congenital heart defects in Down syndrome","volume":"4","year":"2020","journal-title":"Genet. Appl."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Devi\u0107 Pavli\u0107, S., \u0160verko, R., Bari\u0161i\u0107, A., Mladeni\u0107, T., Vranekovi\u0107, J., Stankovi\u0107, A., Peterlin, A., Peterlin, B., Ostoji\u0107, S., and Pereza, N. (2024). MTHFR Gene Polymorphisms and DNA Methylation in Idiopathic Spontaneous Preterm Birth. Medicina, 60.","DOI":"10.3390\/medicina60122028"},{"key":"ref_82","unstructured":"(2025, November 02). Available online: http:\/\/www.psychometrica.de\/effect_size.html."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.2147\/NDT.S113099","article-title":"Antipsychotic-Associated Weight Gain: Management Strategies and Impact on Treatment Adherence","volume":"13","author":"Dayabandara","year":"2017","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1017\/S1092852918001311","article-title":"High Prevalence of Prediabetes and Metabolic Abnormalities in Overweight or Obese Schizophrenia Patients Treated with Clozapine or Olanzapine","volume":"24","author":"Larsen","year":"2019","journal-title":"CNS Spectr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1348\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:23:58Z","timestamp":1769837038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,29]]},"references-count":84,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031348"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031348","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,29]]}}}