Abstract
Insulin resistance is a metabolic disorder and a key factor in the pathogenesis of conditions such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and atherosclerosis. Risk factors for insulin resistance include genetic and environmental influences, such as overweight/obesity, low physical activity, and the use of certain medications, including glucocorticosteroids or antipsychotics.
Antipsychotics (neuroleptics) are widely used in the treatment of various mental disorders, primarily schizophrenia, and such therapy is often lifelong. Due to the mechanism of action via receptors, including serotonergic, muscarinic, and histaminergic, atypical (second-generation) antipsychotics cause metabolic disorders of varying severity. Clozapine and olanzapine have the worst metabolic profiles and aripiprazole and lurasidone are associated with the mildest profiles. Regardless of the potential for developing metabolic complications from specific antipsychotics, baseline predictors of susceptibility are sought in patients. To date, studies have identified risk factors such as higher body weight, male gender, and non-white ethnicity. In addition, patients with schizophrenia are at greater risk for insulin resistance, as shown in studies involving individuals with a first episode of psychosis. This supports the hypothesis that schizophrenia and diabetes may share a common pathogenesis. Despite clear evidence of an increased risk for insulin resistance and, consequently, metabolic syndrome and high cardiovascular risk, insufficient attention is paid to early diagnosis, prevention, and treatment of carbohydrate and lipid metabolism disorders in patients taking neuroleptics. Improved management in this area could benefit not only physical health but also adherence to medical recommendations and the overall effectiveness of psychiatric treatment.
References
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2. Wichniak A, Dudek D, Heitzman J, i wsp. Redukcja ryzyka metabolicznego u chorych na schizofrenię przyjmujących leki przeciwpsychotyczne – zalecenia Polskiego Towarzystwa Psychiatrycznego. Psychiatr Pol 2019;53(6):1191-1218. doi:10.12740/PP/113222.
3. Dayabandara M., Hanwella R., Ratnatunga, S. et al. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat 2017;13:2231-2241 doi.org/10.2147/NDT.S113099.
4. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 2020;7(1):64-77. doi:10.1016/S2215-0366(19)30416-X.
5. Kosmalski M, Różycka-Kosmalska M, Basiak M, i wsp. Diagnosis and management of hyperglycaemia in patients treated with antipsychotic drugs. Endokrynol Pol 2022;73(5):872-884. doi:10.5603/EP.a2022.0071.
6. Pillinger T, Beck K, Gobjila C, et al. Impaired glucose homeostasis in first-episode schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry 2017;74(3):261-269. doi:10.1001/jamapsychiatry.2016.3803.
7. Vargas E, Joy NV, Carrillo Sepulveda MA. Biochemistry, Insulin Metabolic Effects. StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525983/.
8. Lee SH, Park SY, Choi CS. Insulin resistance: from mechanisms to therapeutic strategies. Diabetes Metab J 2022;46(1):15-37. doi:10.4093/dmj.2021.0280.
9. Rahman MS, Hossain KS, Das S, et al. Role of insulin in health and disease: an update. Int J Mol Sci 2021;22(12):6403. doi:10.3390/ijms22126403.
10. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev 2018;98(4):2133-2223. doi:10.1152/physrev.00063.2017.
11. White MF, Kahn CR. Insulin action at a molecular level - 100 years of progress. Mol Metab 2021;52:101304. doi:10.1016/j.molmet.2021.101304.
12. Dobrowolski P, Prejbisz A, Kuryłowicz A, i wsp. Zespół metaboliczny – nowa definicja i postępowanie w praktyce. Stanowisko PTNT, PTLO, PTL, PTH, PTMR,PTMSŻ, Sekcji Prewencji i Epidemiologii PTK, „Klubu 30” PTK oraz Sekcji Chirurgii Metabolicznej i Bariatrycznej TChP. Nadciśnienie Tętnicze Prakt 2022;8(2):47-72.
13. Li M, Chi X, Wang Y, et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal Transduct Target Ther 2022;7:216. doi:10.1038/s41392-022-01073-0.
14. Freeman AM, Acevedo LA, Pennings N. Insulin Resistance. StatPearls Publishing 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507839/.
15. van Winkel R, De Hert M, Wampers M, et al. Major changes in glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2008;69(3):472-479. doi:10.4088/jcp.v69n0320.
16. Ballon JS, Pajvani UB, Mayer LE, et al. Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo. J Psychopharmacol 2018;32(5):533-540. doi:10.1177/0269881118754708.
17. Hahn MK, Wolever TM, Arenovich T, et al. Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol 2013;33(6):740-746. doi:10.1097/JCP.0b013e31829e8333.
18. Teff, K. L., Rickels, M. R., Grudziak, J., et al. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain or psychiatric disease. Diabetes 2013; 62(9), 3232–3240. doi:10.2337/db13 0430
19. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014;6(1):a009191. doi:10.1101/cshperspect.a009191.
20. Chen J, Huang XF, Shao R, et al. Molecular mechanisms of antipsychotic drug-induced diabetes. Front Neurosci 2017;11:643. doi:10.3389/fnins.2017.00643.
21. Engl J, Laimer M, Niederwanger A, et al. Olanzapine impairs glycogen synthesis and insulin signaling in L6 skeletal muscle cells. Mol Psychiatry 2005;10(12):1089-1096. doi:10.1038/sj.mp.4001729.
22. Panariello F, Perruolo G, Cassese A, et al. Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance. J Cell Physiol
2012;227(4):1485-1492. doi:10.1002/jcp.22864.
23. Bushe CJ, Slooff CJ, Haddad PM, et al. Weight change from 3-year observational data: findings from the worldwide schizophrenia outpatient health outcomes database.
J Clin Psychiatry 2012;73(6):e749. doi:10.4088/JCP.11m07246.
24. Sudar FP Zekerallah SS, Paulzen M, et al. Unraveling antipsychotic induced weight gain in schizophrenia – A proof-of-concept study exploring the impact of the cumulative historical occupancy of different receptors by antipsychotics. Psychiatry Res 2025, 348, 116452. doi.org/10.1016/j.psychres.2025.116452.
25. Na J., Park B. S., Jang D., et al. Distinct Firing Activities of the Hypothalamic Arcuate Nucleus Neurons to Appetite Hormones. Int J Mol Sci 2022, 23(5), 2609. doi.org/10.3390/ijms23052609.
26. Mukherjee S, Skrede S, Milbank E, et al. Understanding the Effects of Antipsychotics on Appetite Control. Front Nutr 2022;8:815456. doi:10.3389/fnut.2021.815456.
27. Carnovale C, Lucenteforte E, Battini V, et al. Association between the glyco-metabolic adverse effects of antipsychotic drugs and their chemical and pharmacological profile: a network meta-analysis and regression. Psychol Med 2022;52(10):3768-3780. doi:10.1017/S0033291721000180.
28. Gautam D, Gavrilova O, Jeon J et al. Beneficial metabolic effects of M3 muscarinic acetylcholine receptor deficiency. Cell Metab 2006 Nov;4(5):363-75. doi: 10.1016/j.cmet.2006.09.008..
29. Wallace TJ, Zai CC, Brandl EJ, Müller DJ. Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain. Pharmgenomics Pers Med. 2011;4:83-93. doi:
10.2147/PGPM.S11866.
30. Müller DJ, Zai CC, Sicard M, Remington E, et al. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J. 2012 Apr;12(2):156-64. doi: 10.1038/tpj.2010.65.
31. Galic, S., Oakhill, J. S., Steinberg, G. R. et al. Adipose tissue as an endocrine organ. Mol. Cell. Endocrinol 2010, 316(2), 129–139. doi:10.1016/j.mce.2009.08.018.
32. Fryk E, Olausson J, Mossberg K, et al. Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: a mechanistic case-control and a population-based cohort study. EBioMedicine 2021;65:103264. doi:10.1016/j.ebiom.2021.103264.
33. Verma S, Hussain ME. Obesity and diabetes: an update. Diabetes Metab Syndr 2017;11(Suppl 1):73-79. doi:10.1016/j.dsx.2016.06.017.
34. Davey K, Cotter P, O’Sullivan O, et al. Antipsychotics and the gut microbiome: olanzapine induced metabolic dysfunction is attenuated by antibiotic administration in the rat. Transl Psychiatry 2013;3:e309. doi:10.1038/tp.2013.83.
35. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on
human gut bacteria. Nature 2018, 555:623–8. doi: 10.1038/nature25979.
36. Weston-Green K, Huang XF, Deng C. Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor. CNS Drugs 2013;27(12):1069-1080. doi:10.1007/s40263-013-0115-5.
37. Ozasa R, Okada T, Nadanaka S, et al. The antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic β cells by blocking PERK-mediated translational attenuation. Cell Struct Funct 2013;38(2):183-195. doi:10.1247/csf.13012.
38. Perry BI, McIntosh G, Weich S, et al. The association between first-episode psychosis and abnormal glycaemic control: systematic review and meta-analysis. Lancet Psychiatry 2016;3(11):1049-1058. doi:10.1016/S2215-0366(16)30262 0.
39. Yang W, Zheng L, Zheng B, et al. A meta-analysis of abnormal glucose metabolism in first-episode drug-naive schizophrenia. Psychiatr Danub 2020;32(1):46-54. doi:10.24869/psyd.2020.46.
40. Petrikis P, Tigas S, Tzallas AT, et al. Parameters of glucose and lipid metabolism at the fasted state in drug-naïve first-episode patients with psychosis: evidence for insulin resistance. Psychiatry Res 2015;229(3):901-904. doi:10.1016/j.psychres.2015.07.041.
41. Drexhage RC, Knijff EM, Padmos RC, et al. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder. Expert Rev Neurother 2010; 10: 59–76. doi: 10.1586/ern.09.144.
42. Marcinowicz P, Więdłocha M, Zborowska N, i wsp. A meta-analysis of the influence of antipsychotics on cytokines levels in first episode psychosis. J Clin Med 2021;10(11):2488. doi:10.3390/jcm10112488.
43. Ouabbou S, He Y, Butler K, et al. Inflammation in mental disorders: is the microbiota the missing link? Neurosci Bull 2020;36(9):1071-1084. doi:10.1007/s12264-020-00535-1.
44. Schwarz E, Steiner J, Guest PC, et al. Investigation of molecular serum profiles associated with predisposition to antipsychotic-induced weight gain. World J Biol Psychiatry 2015;16(1):22-30. doi:10.3109/15622975.2014.911298.
45. Kosmas CE, Sourlas A, Oikonomakis K, et al. Biomarkers of insulin sensitivity/resistance. J Int Med Res 2024;52(10):1285550. doi:10.1177/03000605241285550.
46. Steiner J, Berger M, Guest PC, et al. Assessment of insulin resistance among drug-naive patients with first-episode schizophrenia in the context of hormonal stress axis activation. JAMA Psychiatry 2017;74(9):968. doi:10.1001/jamapsychiatry.2017.1983.
47. Lin C, Chen K, Zhang R, et al. The prevalence, risk factors, and clinical characteristics of insulin resistance in Chinese patients with schizophrenia. Compr Psychiatry 2020;96:152145. doi:10.1016/j.comppsych.2019.152145.
48. Guina J, Roy S, Gupta A, et al. Oral glucose tolerance test performance in olanzapine-treated schizophrenia-spectrum patients is predicted by BMI and triglycerides but not olanzapine dose or duration. Hum Psychopharmacol 2017 Jul;32(4). doi: 10.1002/hup.2604. Epub 2017 Jun 1. PMID: 28573760.
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