Metabolic syndrome in adolescents with mental disorders: diagnostics, prevention and treatment

Over the past decades the prevalence of metabolic syndrome (MS) among adolescents has increased significantly. Psychiatric disorders and treatment with psychopharmacological drugs are among the risk factors for the development of MS. The risks of drug-induced metabolic disturbances in adolescents are higher than in adults. Conversely, potential reversibility of MS at its initial stages emphasizes the importance of early detection and treatment. The aim of this narrative review is to summarize the available data on the diagnostics, prevention and treatment of MS in adolescents with mental disorders. Medline and RSCI electronic databases were searched to identify relevant sources of information. Synthesis of information based on 157 publications demonstrates the lack of universally accepted criteria for the diagnosis of MS in adolescents and the limited data on effective preventive or therapeutic interventions. In this review the diagnostics of the components of MS and associated disturbances in adolescents are overviewed, pharmacological and nonpharmacological approaches to MS prophylaxis and treatment are discussed. The results of the reviewed studies reveal a number of factors contributing to the development and progression of MS (both unmodifiable and modifiable): genetic, systemic immune-inflammatory, environmental, pharmacological. Further exploration of these factors in adolescents with mental disorders, as well as the development of preventive and therapeutic strategies based on these factors, are important directions for future research.

1. Doskina EV. Metabolic syndrome is very serious! Diabet. Obraz zhizni. 2007;3:57-59. (In Russ.).

2. Клинические рекомендации «Неалкогольная жировая болезнь печени у взрослых». Рубрикатор клинических рекомендаций. [www.cr.minzdrav. gov.ru]. minzdrav; 2024 [процитировано 07 октября 2024]. Доступно: https://cr.minzdrav.gov.ru/schema/748_1

3. Клинические рекомендации «Сахарный диабет 2 типа у детей». Рубрикатор клинических рекомендаций. [www.cr.minzdrav.gov.ru]. minzdrav; 2024 [процитировано 07 октября 2024]. Доступно: https://cr.minzdrav.gov.ru/recomend/622_5

4. Kondrat’eva E.I., Odinaeva N.D., Drozdova A.I., Kulevatova A.Yu., Vasina E.V. Metabolicheskii sindrom u detei i podrostkov. Uchebnoe posobie. GBUZ Moskovskoi oblasti «Nauchno-issledovatel’skii klinicheskii institut detstva Minzdrava Moskovskoi oblasti». 2022 (In Russ.).

5. Leont’eva IV. Metabolic syndrome in children and adolescents: controversial issues. Pediatriya. 2010;89(2):146-150 (In Russ.).

6. Mazo GE, Kibitov AO. Risk management of metabolic disorders in the use of antipsychotics. Obozrenie psikhiatrii i meditsinskoi psikhologii imeni V.M. 2016;(3):85-97. (In Russ.).

7. The IDF consensus worldwide definition of the metabolic syndrome. Obesity and metabolism. 2005;2(3):47-49. (In Russ.). https://doi.org/10.14341/2071-8713-4854

8. Popov MYu. Long-Term Consequences of Psychopharmacological Treatment in Adolescence: Minimizing Potential Risks. Sovremennaya terapiya psikhicheskikh rasstroistv. 2024;3:58-69. (In Russ.). https://doi.org/10.21265/PSYPH.2024.65.78.006

9. Ahrens W, Moreno LA, Mårild S, Molnár D, Siani A, De Henauw S, et al. Metabolic syndrome in young children: definitions and results of the IDEFICS study. Int J Obes (Lond). 2014;38(Suppl 2):4-14. https://doi.org/10.1038/ijo.2014.130

10. Akinola PS, Tardif I, Leclerc J. Antipsychotic-Induced Metabolic Syndrome: A Review. Metab Syndr Relat Disord. 2023;21(6):294-305. https://doi.org/10.1089/met.2023.0003

11. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640-1645. https://doi.org/10.1161/CIRCULATIONAHA.109.192644а

12. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601. https://doi.org/10.2337/diacare.27.2.596

13. Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA et al. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016;73(9):928-937. https://doi.org/10.1001/jamapsychiatry.2016.1232

14. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249-264. https://doi.org/10.1111/j.1527-3458.2001.tb00198.x

15. Arango C, Ng-Mak D, Finn E, Byrne A, Loebel A. Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis. Eur Child Adolesc Psychiatry. 2020;29(9):1195-1205. https://doi.org/10.1007/s00787-019-01425-2

16. Ataie-Jafari A, Heshmat R, Kelishadi R, Ardalan G, Mahmoudarabi M, Rezapoor A, et al. Generalized or abdominal obesity: which one better identifies cardiometabolic risk factors among children and adolescents? The CASPIAN III study. J Trop Pedi- atr. 2014;60(5):377-385. https://doi.org/10.1093/tropej/fmu033,

17. Ballaz S, Bourin M. Anti-Inflammatory Therapy as a Promising Target in Neuropsychiatric Disorders. Adv Exp Med Biol. 2023;1411:459-486. https://doi.org/10.1007/978-981-19-7376-5_20

18. Bao AM, Meynen G, Swaab DF. The stress sys- tem in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev. 2008;57(2):531-553. https://doi.org/10.1016/j.brainresrev.2007.04.005

19. Barak N, Beck Y, Albeck JH. Betahistine decreases olanzapine-induced weight gain and somnolence in humans. J Psychopharmacol. 2016;30(3):237-241. https://doi.org/10.1177/0269881115626349

20. Belei O, Olariu L, Dobrescu A, Marcovici T, Mar- ginean O. The relationship between non-alcoholic fatty liver disease and small intestinal bacterial overgrowth among overweight and obese chil- dren and adolescents. J Pediatr Endocrinol Metab. 2017;30(11):1161-1168. https://doi.org/10.1515/jpem-2017-0252

21. Bellia A, Giardina E, Lauro D, Tesauro M, Di Fede G, Cusumano G, et al. «The Linosa Study»: epidemiological and heritability data of the metabolic syndrome in a Caucasian genetic isolate. Nutr Metab Cardiovasc Dis. 2009;19(7):455-461. https://doi.org/10.1016/j.numecd.2008.11.002

22. Björntorp P, Rosmond R. The metabolic syndrome--a neuroendocrine disorder? Br J Nutr. 2000;83(Suppl 1):S49-S57. https://doi.org/10.1017/s0007114500000957

23. Boiko AS, Pozhidaev IV, Paderina DZ, Mednova IA, Goncharova AA, Fedorenko OY, et al. Gene Polymorphisms of Hormonal Regulators of Metabolism in Patients with Schizophrenia with Metabolic Syndrome. Genes (Basel). 2022;13(5):844. https://doi.org/10.3390/genes13050844

24. Borghi C, Agnoletti D, Cicero AFG, Lurbe E, Virdis A. Uric Acid and Hypertension: a Review of Evidence and Future Perspectives for the Management of Cardiovascular Risk. Hypertension. 2022;79(9):1927-1936. https://doi.org/10.1161/HYPERTENSIONAHA.122.17956

25. Bovolini A, Garcia J, Andrade MA, Duarte JA. Metabolic Syndrome Pathophysiology and Predisposing Factors. Int J Sports Med. 2021;42(3):199- 214. https://doi.org/10.1055/a-1263-0898

26. Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol. 2011;22(3):165-170. https://doi.org/10.1097/MOL.0b013e3283453e41

27. Burgert TS, Taksali SE, Dziura J, Goodman TR, Yeckel CW, Papademetris X, et al. Alanine ami- notransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adi- ponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91(11):4287-4294. https://doi.org/10.1210/jc.2006-1010

28. Bussler S, Penke M, Flemming G, Elhassan YS, Kratzsch J, Sergeyev E, et al. Novel Insights in the Metabolic Syndrome in Childhood and Adolescence. Horm Res Paediatr. 2017;88(3-4):181-193. https://doi.org/10.1159/000479510

29. Carmona-Vazquez CR, Ruiz-Garcia M, Pena-Landin DM, Diaz-Garcia L, Greenawalt SR. Prevalencia de obesidad y sindrome metabolico en pacientes pediatricos con epilepsia tratados en monoterapia con acido valproico. Rev Neurol. 2015;61(5):193-201. (In Spanish).

30. Carnovale C, Battini V, Santoro C, Riccio MP, Carucci S, Nobile M, et al. Umbrella Review: Association Between Antipsychotic Drugs and Metabolic Syndrome Hallmarks in Children and Adolescents. J Am Acad Child Adolesc Psychiatry. 2024;63(3):313-335. https://doi.org/10.1016/j.jaac.2023.04.018

31. Catalano PM. The impact of gestational diabetes and maternal obesity on the mother and her off- spring. J Dev Orig Health Dis. 2010;1(4):208-215. https://doi.org/10.1017/S2040174410000115

32. Clemente MG, Mandato C, Poeta M, Vajro P. Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions. World J Gastroenterol. 2016;22(36):8078- 8093. https://doi.org/10.3748/wjg.v22.i36.8078

33. Cockerill RG, Biggs BK, Oesterle TS, Croarkin PE. Antidepressant use and body mass index change in overweight adolescents: a historical cohort study. Innov Clin Neurosci. 2014;11(11-12):14-21.

34. Codazzi V, Frontino G, Galimberti L, Giustina A, Petrelli A. Mechanisms and risk factors of metabolic syndrome in children and adolescents. Endocrine. 2024;84(1):16-28. https://doi.org/10.1007/s12020-023-03642-x

35. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988- 1994. Arch Pediatr Adolesc Med. 2003;157(8):821-827. https://doi.org/10.1001/archpedi.157.8.821

36. Correll CU, Findling RL, Tocco M, Pikalov A, Deng L, Goldman R. Safety and effectiveness of lurasidone in adolescents with schizophrenia: results of a 2-year, open-label extension study. CNS Spectr. 2022;27(1):118-128. https://doi.org/10.1017/S1092852920001893

37. Correll CU, Sikich L, Reeves G, Johnson J, Keeton C, Spanos M, et al. Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry. 2020;19(1):69-80. https://doi.org/10.1002/wps.20714

38. Cruz ML, Goran MI. The metabolic syndrome in children and adolescents. Curr Diab Rep. 2004;4(1):53-62. https://doi.org/10.1007/s11892-004-0012-x

39. De Boer MD. Assessing and Managing the Metabolic Syndrome in Children and Adolescents. Nutrients. 2019;11(8):1788. https://doi.org/10.3390/nu11081788

40. de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW, Rifai N. Prevalence of the metabolic syndrome in American adolescents: findings from the Third National Health and Nutrition Examination Survey. Circulation. 2004;110(16):2494-2497. https://doi.org/10.1161/01.CIR.0000145117.40114.C7

41. De Hert M, Correll CU, Bobes J, Cetkovich-Bakmas M, Cohen D, Asai I, et al. Physical illness in patients with severe mental disorders. I. Prevalence, impact of medications and disparities in health care. World Psychiatry. 2011;10(1):52-77. https://doi.org/10.1002/j.2051-5545.2011.tb00014.x

42. De Hert M, Dobbelaere M, Sheridan EM, Cohen D, Correll CU. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: A systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry. 2011;26(3):144-158. https://doi.org/10.1016/j.eurpsy.2010.09.011

43. De Hert M, Schreurs V, Sweers K, Van Eyck D, Hanssens L, Sinko S, et al. Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review. Schizophr Res. 2008;101(1-3):295-303. https://doi.org/10.1016/j.schres.2008.01.028

44. DelBello MP, Kadakia A, Heller V, Singh R, Hagi K, Nosaka T, et al. Systematic Review and Network Meta-analysis: Efficacy and Safety of Second-Generation Antipsychotics in Youths With Bipolar Depression. J Am Acad Child Adolesc Psychiatry. 2022;61(2):243-254. https://doi.org/10.1016/j.jaac.2021.03.021

45. De Melo LGP, Nunes SOV, Anderson G, Vargas HO, Barbosa DS, Galecki P, et al. Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:34-50. https://doi.org/10.1016/j.pnpbp.2017.04.027

46. Devlin AM, Ngai YF, Ronsley R, Panagiotopoulos C. Cardiometabolic risk and the MTHFR C677T variant in children treated with second-generation antipsychotics. Transl Psychiatry. 2012;2(1):e71. https://doi.org/10.1038/tp.2011.68

47. Duncan GE, Li SM, Zhou XH. Prevalence and trends of a metabolic syndrome phenotype among u.s. Adolescents, 1999-2000. Diabetes Care. 2004;27(10):2438-2443. https://doi.org/10.2337/diacare.27.10.2438

48. Fadzlina AA, Harun F, Nurul Haniza MY, Al Sadat N, Murray L, Cantwell MM, et al. Metabolic syndrome among 13 year old adolescents: prevalence and risk factors. BMC Public Health. 2014;14(Suppl 3):7. https://doi.org/10.1186/1471-2458-14-S3-S7

49. Fahed G, Aoun L, Bou Zerdan M, Allam S, Bou Zerdan M, Bouferraa Y, et al. Metabolic Syndrome: Updates on Pathophysiology and Management in 2021. Int J Mol Sci. 2022;23(2):786. https://doi.org/10.3390/ijms23020786

50. Farpour-Lambert NJ, Aggoun Y, Marchand LM, Martin XE, Herrmann FR, Beghetti M. Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children. J Am Coll Cardiol. 2009;54(25):2396-406. https://doi.org/10.1016/j.jacc.2009.08.030

51. Fatima Y, Doi SA, Mamun AA. Sleep quality and obesity in young subjects: a meta-analysis. Obes Rev. 2016;17(11):1154-1166. https://doi.org/10.1111/obr.12444

52. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(Suppl 11):37-41.

53. Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia A, et al. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br J Psychiatry. 2009;194(5):434-438. https://doi.org/10.1192/bjp.bp.108.052605

54. Findling RL, McKenna K, Earley WR, Stankowski J, Pathak S. Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2012;22(5):327- 342. https://doi.org/10.1089/cap.2011.0092

55. Flemming GM, Bussler S, Körner A, Kiess W. Definition and early diagnosis of metabolic syndrome in children. J Pediatr Endocrinol Metab. 2020;33(7):821-833. https://doi.org/10.1515/jpem-2019-0552.

56. Ford ES, Ajani UA, Mokdad AH. National Health and Nutrition Examination. The metabolic syndrome and concentrations of C-reactive protein among U.S. youth. Diabetes Care. 2005;28(4):878- 881. https://doi.org/10.2337/diacare.28.4.878

57. Goh KK, Chen CH, Lu ML. Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: meta-analysis of randomised controlled trials. Int J Psychiatry Clin Pract. 2019;23(1):14-32. https://doi.org/10.1080/13651501.2018.1449864

58. Gotlib D, Ramaswamy R, Kurlander JE, DeRiggi A, Riba M. Valproic Acid in Women and Girls of Childbearing Age. Curr Psychiatry Rep. 2017;19(9):58. https://doi.org/10.1007/s11920-017-0809-3

59. Gouveia ÉR, Gouveia BR, Marques A, Peralta M, França C, Lima A, et al. Predictors of Metabolic Syndrome in Adults and Older Adults from Am- azonas, Brazil. Int J Environ Res Public Health. 2021;18(3):1303. https://doi.org/10.3390/ijerph18031303

60. Graham RC, Burke A, Stettler N. Ethnic and sex differences in the association between metabolic syndrome and suspected nonalcoholic fatty liv- er disease in a nationally representative sample of US adolescents. J Pediatr Gastroenterol Nutr. 2009;49(4):442-449. https://doi.org/10.1097/MPG.0b013e31819f73b4

61. Gramaglia C, Gambaro E, Bartolomei G, Camera P, Chiarelli-Serra M, Lorenzini L, et al. Increased Risk of Metabolic Syndrome in Antidepressants Users: A Mini Review. Front Psychiatry. 2018;9:621. https://doi.org/10.3389/fpsyt.2018.00621

62. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and man- agement of the metabolic syndrome: an Ameri- can Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-2752. https://doi.org/10.1161/CIRCULA - TIONAHA.105.169404

63. Gupta R, Bhangoo A, Matthews NA, Anhalt H, Matta Y, Lamichhane B, Malik S, et al. The prevalence of non-alcoholic fatty liver disease and metabolic syndrome in obese children. J Pediatr Endocrinol Metab. 2011;24(11-12):907-911. https://doi.org/10.1515/jpem.2011.282

64. Gurka MJ, Guo Y, Filipp SL, DeBoer MD. Metabolic syndrome severity is significantly associated with future coronary heart disease in Type 2 diabetes. Cardiovasc Diabetol. 2018;17(1):17. https://doi.org/10.1186/s12933-017-0647-y

65. Hagi K, Nosaka T, Dickinson D, Lindenmayer JP, Lee J, Friedman J, et al. Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2021;78(5):510-518. https://doi.org/10.1001/jamapsychiatry.2021.0015

66. Handen BL, Anagnostou E, Aman MG, Sanders KB, Chan J, Hollway JA, et al. A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension. J Am Acad Child Adolesc Psychiatry. 2017;56(10):849-856.e6. https://doi.org/10.1016/j.jaac.2017.07.790

67. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150(6):1115-1121. https://doi.org/10.1016/j.ahj.2005.02.007

68. Henneman P, Aulchenko YS, Frants RR, van Dijk KW, Oostra BA, van Duijn CM. Prevalence and heritability of the metabolic syndrome and its individual components in a Dutch isolate: the Erasmus Rucphen Family study. J Med Genet. 2008;45(9):572-577. https://doi.org/10.1136/jmg.2008.058388

69. Hjorthøj C, Stürup AE, McGrath JJ, Nordentoft M. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017;4(4):295-301. https://doi.org/10.1016/S2215-0366(17)30078-0

70. Jakobsen KD, Bruhn CH, Pagsberg AK, Fink-Jensen A, Nielsen J. Neurological, Metabolic, and Psychiatric Adverse Events in Children and Adolescents Treated With Aripiprazole. J Clin Psychopharmacol. 2016;36(5):496-499. https://doi.org/10.1097/JCP.0000000000000548

71. Jerrell JM. Neuroendocrine-related adverse events associated with antidepressant treatment in children and adolescents. CNS Neurosci Ther. 2010;16(2):83-90. https://doi.org/10.1111/j.1755-5949.2009.00106.x

72. Johnson RJ, Bakris GL, Borghi C, Chonchol MB, Feldman D, Lanaspa MA, et al. Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation. Am J Kidney Dis. 2018;71(6):851-865. https://doi.org/10.1053/j.ajkd.2017.12.009

73. Kamboj MK, Bonny AE. Polycystic ovary syndrome in adolescence: diagnostic and therapeutic strategies. Transl Pediatr. 2017;6(4):248-255. https://doi.org/10.21037/tp.2017.09.11

74. Kang D, Jing Z, Li R, Hei G, Shao T, Li L, et al. Effect of Betahistine and Metformin on Antipsychotic-Induced Weight Gain: An Analysis of Two Clinical Trials. Front Psychiatry. 2018;9:620. https://doi.org/10.3389/fpsyt.2018.00620

75. Kawai T, Autieri MV, Scalia R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol. 2021;320(3):375-391. https://doi.org/10.1152/ajpcell.00379.2020

76. Khashchenko E, Vysokikh M, Uvarova E, Krechetova L, Vtorushina V, Ivanets T, et al. Activation of Systemic Inflammation and Oxidative Stress in Adolescent Girls with Polycystic Ovary Syndrome in Combination with Metabolic Disorders and Excessive Body Weight. J Clin Med. 2020;9(5):1399. https://doi.org/10.3390/jcm9051399

77. Kim JH, Lim JS. The association between C-reactive protein, metabolic syndrome, and prediabetes in Korean children and adolescents. Ann Pediatr Endocrinol Metab. 2022;27(4):273-280. https://doi.org/10.6065/apem.2142226.113

78. Kim SW, Kang HJ, Jhon M, Kim JW, Lee JY, Walker AJ, Agustini B, Kim JM, Berk M. Statins and Inflammation: New Therapeutic Opportunities in Psychiatry. Front Psychiatry. 2019;10:103. https://doi.org/10.3389/fpsyt.2019.00103

79. Kryzhanovskaya LA, Xu W, Millen BA, Acharya N, Jen KY, Osuntokun O. Comparison of longterm (at least 24 weeks) weight gain and metabol- ic changes between adolescents and adults treated with olanzapine. J Child Adolesc Psychopharmacol. 2012;22(2):157-165. https://doi.org/10.1089/cap.2010.0020

80. Kurtoğlu S, Hatipoğlu N, Mazıcıoğlu M, Kendirici M, Keskin M, Kondolot M. Insulin resistance in obese children and adolescents: HOMA-IR cut-off levels in the prepubertal and pubertal periods. J Clin Res Pediatr Endocrinol. 2010;2(3):100-106. https://doi.org/10.4274/jcrpe.v2i3.100

81. Lalan S, Jiang S, Ng DK, Kupferman F, Warady BA, Furth S, et al. Cardiometabolic Risk Factors, Metabolic Syndrome, and Chronic Kidney Disease Progression in Children. J Pediatr. 2018;202:163- 170. https://doi.org/10.1016/j.jpeds.2018.06.007

82. Laursen TM, Wahlbeck K, Hällgren J, Westman J, Ösby U, Alinaghizadeh H, et al. Life expectancy and death by diseases of the circulatory system in patients with bipolar disorder or schizophrenia in the Nordic countries. PLoS One. 2013;8(6):e67133. https://doi.org/10.1371/journal.pone.0067133

83. Lee J, Kang SC, Kwon O, Hwang SS, Moon JS, Chae HW, et al. Temporal Trends of the Prevalence of Abdominal Obesity and Metabolic Syndrome in Korean Children and Adolescents between 2007 and 2020. JObesMetabSyndr. 2023;32(2):170-178. https://doi.org/10.7570/jomes22059

84. Le Hellard S, Theisen F, Haberhausen M, Raeder MB, Fernø J, Gebhardt S, et al. Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? Mol Psychiatry. 2009;14(3):308-317. https://doi.org/10.1038/sj.mp.4002133

85. Leonard BE. Inflammation as the cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatry. 2013;28:117-126. https://doi.org/10.1159/000343974

86. Li C, Birmaher B, Rooks B, Gill MK, Hower H, Axelson DA, et al. High Prevalence of Metabolic Syndrome Among Adolescents and Young Adults With Bipolar Disorder. J Clin Psychiatry. 2019;80(4):18m12422. https://doi.org/10.4088/JCP.18m12422

87. Li P, Jiang R, Li L, Li X, Liu C, Xu W, et al. Usefulness of hemoglobin A(1c) as a criterion to define metabolic syndrome in nondiabetic Chinese adolescents. J Investig Med. 2013;61(3):586-592. https://doi.org/10.2310/JIM.0b013e318280ab13

88. Li W, Chen D, Peng Y, Lu Z, Kwan MP, Tse LA. Association Between Metabolic Syndrome and Mortality: Prospective Cohort Study. JMIR Public Health Surveill. 2023;9:e44073. https://doi.org/10.2196/44073

89. Li W, Qiu X, Ma H, Geng Q. Incidence and long-term specific mortality trends of metabolic syndrome in the United States. Front Endocrinol (Lausanne). 2023;13:1029736. https://doi.org/10.3389/fendo.2022.1029736

90. Libowitz MR, Nurmi EL. The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children. Front Psychiatry. 2021;12:623681. doi: 10.3389/fpsyt.2021.623681

91. Mameli C, Zuccotti GV, Carnovale C, Galli E, Nannini P, Cervia D, et al. An update on the assessment and management of metabolic syndrome, a growing medical emergency in paediatric populations. Pharmacol Res. 2017;119:99-117. https://doi.org/10.1016/j.phrs.2017.01.017.

92. Marazziti D, Arone A, Palermo S, Annuzzi E, Cappellato G, Chiarantini I, et al. The Wicked Relationship between Depression and Metabolic Syndrome. Clin Neuropsychiatry. 2023;20(2):100- 108. https://doi.org/10.36131/cnfioritieditore20230202.

93. Matricciani L, Paquet C, Galland B, Short M, Olds T. Children’s sleep and health: a meta-review. Sleep Med Rev. 2019;46:136-150. https://doi.org/10.1016/j.smrv.2019.04.011

94. Mazereel V, Detraux J, Vancampfort D, van Winkel R, De Hert M. Impact of Psychotropic Medication Effects on Obesity and the Metabolic Syndrome in People With Serious Mental Illness. Front Endocrinol (Lausanne). 2020;11:573479. https://doi.org/10.3389/fendo.2020.573479

95. McCarthy K, Laird E, O’Halloran AM, Fallon P, O’Connor D, Ortuño RR, et al. An examination of the prevalence of metabolic syndrome in older adults in Ireland: Findings from The Irish Longitudinal Study on Ageing (TILDA). PLoS One. 2022;17(9):e0273948. https://doi.org/10.1371/journal.pone.0273948

96. Medina-Vera I, Serralde-Zúñiga AE, Islas-Ortega L, Jiménez-Rolland E, Jimenez-Chanes KD, Guevara-Cruz M. Diagnosis of metabolic syndrome in children as a potential indicator of technical ability in medical and nutritional care. Nutr Hosp. 2015;32(5):2105-2110. https://doi.org/10.3305/nh.2015.32.5.9703

97. Mehdi S, Wani SUD, Krishna KL, Kinattingal N, Roohi TF. A review on linking stress, depression, and insulin resistance via low-grade chronic inflammation. Biochem Biophys Rep. 2023;36:101571. https://doi.org/10.1016/j.bbrep.2023.101571

98. Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: definition, pathophysiology, and mechanisms. Am Heart J. 2005;149(1):33-45. https://doi.org/10.1016/j.ahj.2004.07.013

99. Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M. Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull. 2013;39(2):295-305. https://doi.org/10.1093/schbul/sbs082

100. Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, De Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull. 2013;39(2):306-318. https://doi.org/10.1093/schbul/sbr148

101. Moreira FP, Jansen K, Cardoso TA, Mondin TC, Magalhães PVDS, Kapczinski F, et al. Metabolic syndrome in subjects with bipolar disorder and major depressive disorder in a current depressive episode: Population-based study: Metabolic syn- drome in current depressive episode. J Psychiatr Res. 2017;92:119-123. https://doi.org/10.1016/j.jpsychires.2017.03.025

102. Murdock KW, LeRoy AS, Fagundes CP. Inhibi- tion is associated with metabolic syndrome and depression through inflammation. Stress Health. 2018;34(3):457-461. https://doi.org/10.1002/smi.2808

103. Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Effica- cy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analy- sis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:79-85. https://doi.org/10.1016/j.pnpbp.2013.09.006

104. Nehus E, Mitsnefes M. Childhood Obesity and the Metabolic Syndrome. Pediatr Clin North Am. 2019;66(1):31-43. https://doi.org/10.1016/j.pcl.2018.08.004

105. Nehus E. Obesity and chronic kidney disease. Curr Opin Pediatr. 2018;30(2):241-246. https://doi.org/10.1097/MOP.0000000000000586

106. Noubiap JJ, Nansseu JR, Lontchi-Yimagou E, Nkeck JR, Nyaga UF, Ngouo AT, et al. Global, regional, and country estimates of metabolic syndrome burden in children and adolescents in 2020: a systematic review and modelling analysis. Lancet Child Adolesc Health. 2022;6(3):158-170. https://doi.org/10.1016/S2352-4642(21)00374-6

107. Nussbaum LA, Dumitraşcu V, Tudor A, Grădinaru R, Andreescu N, Puiu M. Molecular study of weight gain related to atypical antipsychotics: clinical implications of the CYP2D6 genotype. Rom J Morphol Embryol. 2014;55(3):877-884.

108. Ottesen NM, Meluken I, Frikke-Schmidt R, Plomgaard P, Scheike T, Fernandes BS, et al. Are remitted affective disorders and familial risk of affective disorders associated with metabolic syndrome, inflammation and oxidative stress?—a monozygotic twin study. Psychol Med. 2020;50(10):1736-1745. https://doi.org/10.1017/S003329171900182X

109. Parksepp M, Haring L, Kilk K, Taalberg E, Kangro R, Zilmer M, et al. Marked Low-GradeInflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five Year Follow-Up Study. Metabolites. 2022;12(10):983. https://doi.org/10.3390/metabo12100983

110. Patel RS, Majumder P, Correll CU. Characteristics and Correlates of Metabolic Syndrome in Adolescents with Unipolar and Bipolar Depression: Results from a Cross-National Inpatient Case-Control Study. J Child Adolesc Psychopharmacol. 2022;32(8):426-433. https://doi.org/10.1089/cap.2022.0017

111. Peng TR, Lin HH, Lee MC, Chen SM. Statins as an adjuvant therapy for patients with schizophrenia: An up-to-date systematic review and meta-analysis. Gen Hosp Psychiatry. 2024;89:75-83. https://doi.org/10.1016/j.genhosppsych.2024.05.001

112. Perry BI, Burgess S, Jones HJ, Zammit S, Upthegrove R, Mason AM, et al. The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study. PLoS Med. 2021;18(3):e1003455. https://doi.org/10.1371/journal.pmed.1003455

113. Piras M, Chahma J, Ranjbar S, Laaboub N, Grosu C, Plessen KJ, et al. Is Clozapine-induced Weight Gain Dose-dependent? Results From a Prospective Cohort Study. Schizophr Bull. 2023;49(4):944-952. https://doi.org/10.1093/schbul/sbad009

114. Podeanu MA, Turcu-Stiolica A, Subțirelu MS, Stepan MD, Ionele CM, Gheonea DI, et al. C-Reactive Protein as a Marker of Inflammation in Children and Adolescents with Metabolic Syndrome: A Systematic Review and Meta-Analysis. Biomedicines. 2023;11(11):2961. https://doi.org/10.3390/biomedicines11112961

115. Poyurovsky M, Fuchs C, Pashinian A, Levi A, Weizman R, Weizman A. Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination. Psychopharmacology (Berl). 2013;226(3):615-622. https://doi.org/10.1007/s00213-012-2935-2

116. Pozzi M, Ferrentino RI, Scrinzi G, Scavone C, Capuano A, Radice S, et al. Weight and body mass index increase in children and adolescents exposed to antipsychotic drugs in non-interventional settings: a meta-analysis and meta-regression. Eur Child Adolesc Psychiatry. 2022;31(1):21-37. https://doi.org/10.1007/s00787-020-01582-9

117. Qin B, Zhang Y, Zhou X, Cheng P, Liu Y, Chen J, et al. Selective serotonin reuptake inhibitors versus tricyclic antidepressants in young patients: a meta-analysis of efficacy and acceptability. Clin Ther. 2014;36(7):1087-1095.e4. https://doi.org/10.1016/j.clinthera.2014.06.001

118. Quteineh L, Vandenberghe F, Saigi Morgui N, Delacrétaz A, Choong E, Gholam-Rezaee M, et al. Impact of HSD11B1 polymorphisms on BMI and components of the metabolic syndrome in patients receiving psychotropic treatments. Pharmacogenet Genomics. 2015;25(5):246-258. https://doi.org/10.1097/FPC.0000000000000131

119. Ramírez-Garza SL, Laveriano-Santos EP, Moreno JJ, Bodega P, de Cos-Gandoy A, de Miguel M, et al. Metabolic syndrome, adiposity, diet, and emotional eating are associated with oxidative stress in adolescents. Front Nutr. 2023;10:1216445. https://doi.org/10.3389/fnut.2023.1216445

120. Reekie J, Hosking SP, Prakash C, Kao KT, Juonala M, Sabin MA. The effect of antidepressants and antipsychotics on weight gain in children and adolescents. Obes Rev. 2015;16(7):566-580. https://doi.org/10.1111/obr.12284

121. Reinehr T, Lass N, Toschke C, Rothermel J, Lan- zinger S, Holl RW. Which Amount of BMI-SDS Reduction Is Necessary to Improve Cardiovascular Risk Factors in Overweight Children? J Clin Endo- crinol Metab. 2016;101(8):3171-3179. https://doi.org/10.1210/jc.2016-1885

122. Reisinger C, Nkeh-Chungag BN, Fredriksen PM, Goswami N. The prevalence of pediatric metabolic syndrome-a critical look on the discrepancies be- tween definitions and its clinical importance. Int J Obes (Lond). 2021;45(1):12-24. https://doi.org/10.1038/s41366-020-00713-1

123. Rizzo NS, Ruiz JR, Oja L, Veidebaum T, Sjöström M. Associations between physical activity, body fat, and insulin resistance (homeostasis model assess- ment) in adolescents: the European Youth Heart Study. Am J Clin Nutr. 2008;87(3):586-592. https://doi.org/10.1093/ajcn/87.3.586

124. Rocha EPAA, Vogel M, Stanik J, Pietzner D, Wil- lenberg A, Körner A, et al. Serum Uric Acid Lev- els as an Indicator for Metabolically Unhealthy Obesity in Children and Adolescents. Horm Res Paediatr. 2018;90(1):19-27. https://doi.org/10.1159/000490113

125. Rodríguez LA, Madsen KA, Cotterman C, Lustig RH. Added sugar intake and metabolic syndrome in US adolescents: cross-sectional analysis of the National Health and Nutrition Examination Survey 2005- 2012. Public Health Nutr. 2016;19(13):2424-2434. https://doi.org/10.1017/S1368980016000057

126. Saadullah Khani N, Cotic M, Wang B, Abidoph R, Mills G, Richards-Belle A, et al. Schizophrenia and cardiometabolic abnormalities: A Mendelian randomization study. Front Genet. 2023;14:1150458. https://doi.org/10.3389/fgene.2023.1150458

127. Sadeghi HM, Adeli I, Calina D, Docea AO, Mousavi T, Daniali M, et al. Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing. Int J Mol Sci. 2022;23(2):583. https://doi.org/10.3390/ijms23020583

128. Saito Y, Tanaka A, Node K, Kobayashi Y. Uric acid and cardiovascular disease: A clinical review. J Cardiol. 2021;78(1):51-57. https://doi.org/10.1016/j.jjcc.2020.12.013

129. Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep. 2018;20(2):12. https://doi.org/10.1007/s11906-018-0812-z

130. Sayin FK, Buyukinan M. Sleep Duration and Me- dia Time Have a Major Impact on Insulin Resis- tance and Metabolic Risk Factors in Obese Children and Adolescents. Child Obes. 2016;12(4):272-278. https://doi.org/10.1089/chi.2015.0126

131. Scheen AJ. Metabolic disorders induced by psychotropic drugs. Ann Endocrinol (Paris). 2023;84(3):357-363. https://doi.org/10.1016/j.ando.2023.03.006

132. Schuch FB, Vancampfort D. Physical activity, exer- cise, and mental disorders: it is time to move on. Trends Psychiatry Psychother. 2021;43(3):177-184. https://doi.org/10.47626/2237-6089-2021-0237

133. Shapiro M, Reid A, Olsen B, Taasan M, McNamara J, Nguyen M. Topiramate, zonisamide and weight loss in children and adolescents prescribed psychiatric medications: A medical record review. Int J Psychiatry Med. 2016;51(1):56-68. https://doi.org/10.1177/0091217415621266

134. Shen H, Li R, Yan R, Zhou X, Feng X, Zhao M, et al. Adjunctive therapy with statins in schizophre- nia patients: A meta-analysis and implications. Psychiatry Res. 2018;262:84-93. https://doi.org/10.1016/j.psychres.2018.02.018

135. Shnayder NA, Grechkina VV, Trefilova VV, Efremov IS, Dontceva EA, Narodova EA, et al. Valproate-Induced Metabolic Syndrome. Biomedicines. 2023;11(5):1499. https://doi.org/10.3390/biomedicines11051499

136. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review. J Clin Psychiatry. 2009;70(7):1041-1050. https://doi.org/10.4088/jcp.08r04392

137. Siskind D, Hahn M, Correll CU, Fink-Jensen A, Russell AW, Bak N, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: A systematic review and individual participant data meta-analysis. Diabetes Obes Metab. 2019;21(2):293-302. https://doi.org/10.1111/dom.13522

138. Stahl S.M. Prescriber’s Guide: Stahl’s Essential Psychopharmacology, 6th Edition. Cambridge University Press, 2017.

139. Styne DM, Arslanian SA, Connor EL, Farooqi IS, Murad MH, Silverstein JH, et al Pediatric obesity-assessment, treatment, and prevention: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(3):709-757. https://doi.org/10.1210/jc.2016-2573

140. Tagi VM, Samvelyan S, Chiarelli F. Treatment of Metabolic Syndrome in Children. Horm Res Paediatr. 2020;93(4):215-225. https://doi.org/10.1159/000510941

141. Taylor JH, Jakubovski E, Gabriel D, Bloch MH. Predictors and Moderators of Antipsychotic-Related Weight Gain in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study. J Child Adolesc Psychopharmacol. 2018;28(7):474-484. https://doi.org/10.1089/cap.2017.0147

142. Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, et al. Recommendations from the 2023 international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Eur J Endocrinol. 2023;189(2):43-64. https://doi.org/10.1093/ejendo/lvad096

143. Trigueiro AJP, Ramirez J, Hennessey E, Beqiri M. Metabolic Syndrome Identification in Patients Treated With Second-Generation Antipsychotic Medications. J Psychosoc Nurs Ment Health Serv. 2022;60(8):11-18. https://doi.org/10.3928/02793695-20220314-01

144. Upadhyay N, Patel A, Chan W, Aparasu RR, Ochoa-Perez M, Sherer JT, et al. Reversibility of psychotropic medication induced weight gain among children and adolescents with bipolar dis- orders. Psychiatry Res. 2019;276:151-159. https://doi.org/10.1016/j.psychres.2019.05.005

145. Valtonen MK, Laaksonen DE, Laukkanen JA, Tolmunen T, Viinamäki H, Lakka HM, et al. Lowgrade inflammation and depressive symptoms as predictors of abdominal obesity. Scand J Public Health. 2012;40(7):674-680. https://doi.org/10.1177/1403494812461730

146. Vancampfort D, Stubbs B, Mitchell AJ, De Hert M, Wampers M, Ward PB, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bi- polar disorder and major depressive disorder: a systematic review and meta-analysis. World Psy- chiatry. 2015;14(3):339-347. https://doi.org/10.1002/wps.20252

147. Vanlancker T, Schaubroeck E, Vyncke K, Cadenas-Sanchez C, Breidenassel C, González-Gross M, et al. HELENA project group. Comparison of definitions for the metabolic syndrome in adolescents. The HELENA study. Eur J Pediatr. 2017;176(2):241-252. https://doi.org/10.1007/s00431-016-2831-6

148. Viner RM, Segal TY, Lichtarowicz-Krynska E, Hindmarsh P. Prevalence of the insulin resistance syndrome in obesity. Arch Dis Child. 2005;90(1):10-14. https://doi.org/10.1136/adc.2003.036467

149. Walker AJ, Kim Y, Borissiouk I, Rehder R, Dodd S, Morris G, et al. Neurobiological underpinnings and mechanisms in mood disorders. Neurosci Biobehav Rev. 2021;128:693-708. https://doi.org/10.1016/j.neubiorev.2021.07.012

150. Wang HR, Woo YS, Bahk WM. The role of melatonin and melatonin agonists in counteracting antipsychotic-induced metabolic side effects: a systematic review. Int Clin Psychopharmacol. 2016;31(6):301-306. https://doi.org/10.1097/YIC.0000000000000135

151. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23):2362-2374. https://doi.org/10.1056/NEJMoa031049

152. Widjaja NA, Irawan R, Hanindita MH, Ugrasena I, Handajani R. METS-IR vs. HOMA-AD and Metabolic Syndrome in Obese Adolescents. J Med Invest. 2023;70(1.2):7-16. https://doi.org/10.2152/jmi.70.7

153. Yanai H, Adachi H, Hakoshima M, Katsuyama H. Molecular Biological and Clinical Understand- ing of the Pathophysiology and Treatments of Hy- peruricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease. Int J Mol Sci. 2021;22(17):9221. https://doi.org/10.3390/ijms22179221

154. Yang L, Chen J, Li Y, Wang Y, Liang S, Shi Y, et al. Association between SCAP and SREBF1 gene polymorphisms and metabolic syndrome in schizophrenia patients treated with atypical antipsychotics. World J Biol Psychiatry. 2016;17(6):467-474. https://doi.org/10.3109/15622975.2016.1165865

155. Yang L, Chen J, Liu D, Yu S, Cong E, Li Y, et al. Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated pa- tients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:136-141. https://doi.org/10.1016/j.pnpbp.2014.08.015

156. Ye W, Xing J, Yu Z, Hu X, Zhao Y. Mechanism and treatments of antipsychotic-induced weight gain. Int J Obes (Lond). 2023;47(6):423-433. https://doi.org/10.1038/s41366-023-01291-8

157. Zimmet P, Alberti G, Kaufman F, Tajima N, Silink M, Arslanian S, et al. International Diabetes Feder- ation Task Force on Epidemiology and Prevention of Diabetes. The metabolic syndrome in children and adolescents. Lancet. 2007;369(9579):2059-2061. https://doi.org/10.1016/S0140-6736(07)60958-1.