GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9:137–50.

Article  PubMed Central  Google Scholar 

Jauhar S, Johnstone M, Mckenna PJ. Schizophrenia. Lancet. 2022;399:473–86.

Article  CAS  PubMed  Google Scholar 

Ceraso A, Lin JJ, Schneider-Thoma J, Siafis S, Tardy M, Komossa K, et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2020;2020:Cd008016.

PubMed Central  Google Scholar 

Cernea S, Dima L, Correll CU, Manu P. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs. 2020;80:1763–81.

Article  CAS  PubMed  Google Scholar 

Wada M, Noda Y, Iwata Y, Tsugawa S, Yoshida K, Tani H, et al. Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Mol Psychiatry. 2022;27:2950–67.

Article  CAS  PubMed  Google Scholar 

Lähteenvuo M, Tiihonen J. Antipsychotic polypharmacy for the management of schizophrenia: evidence and recommendations. Drugs. 2021;81:1273–84.

Article  PubMed  PubMed Central  Google Scholar 

Henderson DC, Vincenzi B, Andrea NV, Ulloa M, Copeland PM. Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry. 2015;2:452–64.

Article  PubMed  Google Scholar 

Carli M, Kolachalam S, Longoni B, Pintaudi A, Baldini M, Aringhieri S, et al. Atypical antipsychotics and metabolic syndrome: from molecular mechanisms to clinical differences. Pharmaceuticals. 2021;14:238.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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. 2020;11:573479.

Article  Google Scholar 

Vantaggiato C, Panzeri E, Citterio A, Orso G, Pozzi M. Antipsychotics promote metabolic disorders disrupting cellular lipid metabolism and trafficking. Trends Endocrinol Metab. 2019;30:189–210.

Article  CAS  PubMed  Google Scholar 

Rojo LE, Gaspar PA, Silva H, Risco L, Arena P, Cubillos-Robles K, et al. Metabolic syndrome and obesity among users of second generation antipsychotics: A global challenge for modern psychopharmacology. Pharmacol Res. 2015;101:74–85.

Article  CAS  PubMed  Google Scholar 

Ono S, Sugai T, Suzuki Y, Yamazaki M, Shimoda K, Mori T, et al. High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey. BMC Psychiatry. 2018;18:1–7.

Article  Google Scholar 

Masuda T, Misawa F, Takase M, Kane JM, Correll CU. Association with hospitalization and all-cause discontinuation among patients with schizophrenia on clozapine vs other oral second-generation antipsychotics: a systematic review and meta-analysis of cohort studies. JAMA Psychiatry. 2019;76:1052–62.

Article  PubMed  PubMed Central  Google Scholar 

Ferreira V, Folgueira C, Guillén M, Zubiaur P, Navares M, Sarsenbayeva A, et al. Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight. Metabolism. 2022;137:155335.

Article  CAS  PubMed  Google Scholar 

Huang J, Hei GR, Yang Y, Liu CC, Xiao JM, Long YJ, et al. Increased appetite plays a key role in olanzapine-induced weight gain in first-episode schizophrenia patients. Front Pharmacol. 2020;11:739.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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;56:849–56.

Article  PubMed  Google Scholar 

Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS One. 2011;6:e22662.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hahn MK, Wolever TM, Arenovich T, Teo C, Giacca A, Powell V, et al. Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol. 2013;33:740–6.

Article  CAS  PubMed  Google Scholar 

Vucicevic L, Misirkic-Marjanovic M, Paunovic V, Kravic-Stevovic T, Martinovic T, Ciric D, et al. Autophagy inhibition uncovers the neurotoxic action of the antipsychotic drug olanzapine. Autophagy. 2014;10:2362–78.

Article  CAS  PubMed  Google Scholar 

Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nat Rev Endocrinol. 2017;13:710–30.

Article  CAS  PubMed  Google Scholar 

Liu X, Lian J, Hu CH, Deng C. Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways. Pharmacol Res. 2015;100:36–46.

Article  CAS  PubMed  Google Scholar 

Lian J, Huang XF, Pai N, Deng C. Ameliorating antipsychotic-induced weight gain by betahistine: mechanisms and clinical implications. Pharmacol Res. 2016;106:51–63.

Article  CAS  PubMed  Google Scholar 

Liu X, Deng C, Cao S, Gong J, Wang BC, Hu CH. Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats. Life Sci. 2015;128:72–8.

Article  CAS  PubMed  Google Scholar 

Raeder MB, Fernø J, Vik-Mo AO, Steen VM. SREBP activation by antipsychotic-and antidepressant-drugs in cultured human liver cells: relevance for metabolic side-effects. Mol Cell Biochem. 2006;289:167–73.

Article  CAS  PubMed  Google Scholar 

Yang LH, Chen TM, Yu ST, Chen YH. Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharmacol Res. 2007;56:202–8.

Article  CAS  PubMed  Google Scholar 

Polymeropoulos MH, Licamele L, Volpi S, Mack K, Mitkus SN, Carstea ED, et al. Common effect of antipsychotics on the biosynthesis and regulation of fatty acids and cholesterol supports a key role of lipid homeostasis in schizophrenia. Schizophr Res. 2009;108:134–42.

Article  PubMed  Google Scholar 

Skrede S, Fernø J, Vázquez MJ, Fjær S, Pavlin T, Lunder N, et al. Olanzapine, but not aripiprazole, weight-independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol. 2012;15:163–79.

Article  CAS  PubMed  Google Scholar 

Le Hellard S, Mühleisen T, Djurovic S, Fernø J, Ouriaghi Z, Mattheisen M, et al. Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples. Mol Psychiatry. 2010;15:463–72.

Article  PubMed  Google Scholar 

Vassas TJ, Burghardt KJ, Ellingrod VL. Pharmacogenomics of sterol synthesis and statin use in schizophrenia subjects treated with antipsychotics. Pharmacogenomics. 2014;15:61–7.

Article  CAS  PubMed  Google Scholar 

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 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2015;56:136–41.

Article  CAS  PubMed  Google Scholar 

Debose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem Sci. 2018;43:358–68.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu D, Wang Z, Xia Y, Shao F, Xia W, Wei Y, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature. 2020;580:530–5.

Article  CAS  PubMed  Google Scholar 

Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell. 2018;175:133–45.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tirosh A, Tuncman G, Calay ES, Rathaus M, Ron I, Tirosh A, et al. Intercellular transmission of hepatic ER stress in obesity disrupts systemic metabolism. Cell Metab. 2021;33:319–33.

Article  CAS  PubMed  Google Scholar 

Kawamura S, Matsushita Y, Kurosaki S, Tange M, Fujiwara N, Hayata Y, et al. Inhibiting SCAP/SREBP exacerbates liver injury and carcinogenesis in murine nonalcoholic steatohepatitis. J Clin Invest. 2022;132:e151895.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim JY, Wang LQ, Sladky VC, Oh TG, Liu J, Trinh K, et al. PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis. Cell Metab. 2022;34:1548–60.

Article  CAS  PubMed