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Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model

. 2024 Feb ; 30 (2) : e14565.

Language English Country England, Great Britain Media print

Document type Journal Article, Research Support, Non-U.S. Gov't

Grant support
CZ.02.1.01/0.0/0.0/17_043/0009632 MEYS and the OP RDE
MUNI/A/1342/2020 Specific University Research Grant provided by Ministry of Education, Youth and Sports of the Czech Republic
MUNI/A/1342/2022 Specific University Research Grant provided by Ministry of Education, Youth and Sports of the Czech Republic
3SGA5789 SoMoPro II Programme
857560 European Union's Horizon 2020 research and innovation program
EHP-BFNU-OVNKM-3-048-2020 EEA Grants/Norway Grants
EHP-BFNU-OVNKM-4-174-01-2022 EEA Grants/Norway Grants

AIM: Widely used second-generation antipsychotics are associated with adverse metabolic effects, contributing to increased cardiovascular mortality. To develop strategies to prevent or treat adverse metabolic effects, preclinical models have a clear role in uncovering underlying molecular mechanisms. However, with few exceptions, preclinical studies have been performed in healthy animals, neglecting the contribution of dysmetabolic features inherent to psychotic disorders. METHODS: In this study, methylazoxymethanol acetate (MAM) was prenatally administered to pregnant Sprague-Dawley rats at gestational day 17 to induce a well-validated neurodevelopmental model of schizophrenia mimicking its assumed pathogenesis with persistent phenotype. Against this background, the dysmetabolic effects of acute treatment with olanzapine and haloperidol were examined in female rats. RESULTS: Prenatally MAM-exposed animals exhibited several metabolic features, including lipid disturbances. Half of the MAM rats exposed to olanzapine had pronounced serum lipid profile alteration compared to non-MAM controls, interpreted as a reflection of a delicate MAM-induced metabolic balance disrupted by olanzapine. In accordance with the drugs' clinical metabolic profiles, olanzapine-associated dysmetabolic effects were more pronounced than haloperidol-associated dysmetabolic effects in non-MAM rats and rats exposed to MAM. CONCLUSION: Our results demonstrate metabolic vulnerability in female prenatally MAM-exposed rats, indicating that findings from healthy animals likely provide an underestimated impression of metabolic dysfunction associated with antipsychotics. In the context of metabolic disturbances, neurodevelopmental models possess a relevant background, and the search for adequate animal models should receive more attention within the field of experimental psychopharmacology.

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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. PubMed PMC

Cernea S, Dima L, Correll CU, Manu P. Pharmacological management of glucose dysregulation in patients treated with second‐generation antipsychotics. Drugs. 2020;80(17):1763‐1781. PubMed

Horska K, Ruda‐Kucerova J, Skrede S. GLP‐1 agonists: superior for mind and body in antipsychotic‐treated patients? Trends Endocrinol Metab. 2022;33(9):628‐638. doi:10.1016/j.tem.2022.06.005 PubMed DOI

Carli M, Kolachalam S, Longoni B, et al. Atypical antipsychotics and metabolic syndrome: from molecular mechanisms to clinical differences. Pharmaceuticals. 2021;14(3):238. PubMed PMC

Vantaggiato C, Panzeri E, Citterio A, Orso G, Pozzi M. Antipsychotics promote metabolic disorders disrupting cellular lipid metabolism and trafficking. Trends Endocrinol Metab. 2019;3:189‐210. PubMed

Uliana DL, Zhu X, Gomes FV, Grace AA. Using animal models for the studies of schizophrenia and depression: the value of translational models for treatment and prevention. Front Behav Neurosci. 2022;16:935320. doi:10.3389/fnbeh.2022.935320 PubMed DOI PMC

Benarroch L, Kowalchuk C, Wilson V, et al. Atypical antipsychotics and effects on feeding: from mice to men. Psychopharmacology (Berl). 2016;233(14):2629‐2653. doi:10.1007/s00213-016-4324-8 PubMed DOI

Boyda HN, Tse L, Procyshyn RM, Honer WG, Barr AM. Preclinical models of antipsychotic drug‐induced metabolic side effects. Trends Pharmacol Sci. 2010;31(10):484‐497. PubMed

Ersland KM, Myrmel LS, Fjære E, et al. One‐year treatment with olanzapine depot in female rats: metabolic effects. Int J Neuropsychopharmacol. 2019;22(5):358‐369. PubMed PMC

Horska K, Ruda‐Kucerova J, Karpisek M, Suchy P, Opatrilova R, Kotolova H. Depot risperidone‐induced adverse metabolic alterations in female rats. J Psychopharmacol (Oxf). 2017;31(4):487‐499. PubMed

Horska K, Ruda‐Kucerova J, Babinska Z, et al. Olanzapine‐depot administration induces time‐dependent changes in adipose tissue endocrine function in rats. Psychoneuroendocrinology. 2016;73:177‐185. PubMed

Skrede S, Martins L, Berge RK, Steen VM, López M, Fernø J. Olanzapine depot formulation in rat: a step forward in modelling antipsychotic‐induced metabolic adverse effects. Int J Neuropsychopharmacol. 2014;17(1):91‐104. PubMed

Skrede S, Fernø J, Vázquez MJ, et al. Olanzapine, but not aripiprazole, weight‐independently elevates serum triglycerides and activates lipogenic gene expression in female rats. Int J Neuropsychopharmacol. 2012;15(2):163‐179. doi:10.1017/S1461145711001271 PubMed DOI

Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large‐scale meta‐analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163‐180. PubMed PMC

Dieset I, Andreassen OA, Haukvik UK. Somatic comorbidity in schizophrenia: some possible biological mechanisms across the life span. Schizophr Bull. 2016;42(6):1316‐1319. PubMed PMC

Pillinger T, D'Ambrosio E, McCutcheon R, et al. Is psychosis a multisystem disorder? A meta‐review of central nervous system, immune, cardiometabolic, and endocrine alterations in first‐episode psychosis and perspective on potential models. Mol Psychiatry. 2019;24(6):776‐794. PubMed PMC

Vancampfort D, Stubbs B, Mitchell AJ, et al. Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta‐analysis. World Psychiatry. 2015;14(3):339‐347. PubMed PMC

Horska K, Ruda‐Kucerova J, Drazanova E, et al. Aripiprazole‐induced adverse metabolic alterations in polyI:C neurodevelopmental model of schizophrenia in rats. Neuropharmacology. 2017;123:148‐158. PubMed

Du Y, Yu Y, Hu Y, et al. Genome‐wide, integrative analysis implicates exosome‐derived MicroRNA dysregulation in schizophrenia. Schizophr Bull. 2019;45(6):1257‐1266. doi:10.1093/schbul/sby191 PubMed DOI PMC

Du Y, Tan W‐L, Chen L, et al. Exosome transplantation from patients with schizophrenia causes schizophrenia‐relevant behaviors in mice: an integrative multi‐omics data analysis. Schizophr Bull. 2021;47(5):1288‐1299. doi:10.1093/schbul/sbab039 PubMed DOI PMC

Sonnenschein SF, Grace AA. Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia. Neuropharmacology. 2019;163:107632. PubMed PMC

Zhang H‐C, Du Y, Chen L, et al. MicroRNA schizophrenia: etiology, biomarkers and therapeutic targets. Neurosci Biobehav Rev. 2023;146:105064. doi:10.1016/j.neubiorev.2023.105064 PubMed DOI

Young JW, Zhou X, Geyer MA. Animal models of schizophrenia. Curr Top Behav Neurosci. 2010;4:391‐433. doi:10.1007/7854_2010_62 PubMed DOI

Winship IR, Dursun SM, Baker GB, et al. An overview of animal models related to schizophrenia. Can J Psychiatry. 2019;64(1):5‐17. PubMed PMC

Lodge DJ, Grace AA. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res. 2009;204(2):306‐312. PubMed PMC

Micale V, Kucerova J, Sulcova A. Leading compounds for the validation of animal models of psychopathology. Cell Tissue Res. 2013;354(1):309‐330. doi:10.1007/s00441-013-1692-9 PubMed DOI

Castellani LN, Costa‐Dookhan KA, McIntyre WB, et al. Preclinical and clinical sex differences in antipsychotic‐induced metabolic disturbances: a narrative review of adiposity and glucose metabolism. J Psychiatry Brain Sci. 2019;4:e190013. PubMed PMC

Schoretsanitis G, Dubath C, Grosu C, et al. Olanzapine‐associated dose‐dependent alterations for weight and metabolic parameters in a prospective cohort. Basic Clin Pharmacol Toxicol. 2022;130(4):531‐541. doi:10.1111/bcpt.13715 PubMed DOI PMC

Vandenberghe F, Gholam‐Rezaee M, SaigíMorgui N, et al. Importance of early weight changes to predict long‐term weight gain during psychotropic drug treatment. J Clin Psychiatry. 2015;76(11):8736. doi:10.4088/JCP.14m09358 PubMed DOI

Ferreira V, Grajales D, Valverde ÁM. Adipose tissue as a target for second‐generation (atypical) antipsychotics: a molecular view. Biochim Biophys Acta BBA‐Mol Cell Biol Lipids. 2020;1865(2):158534. PubMed

Grajales D, Ferreira V, Valverde ÁM. Second‐generation antipsychotics and dysregulation of glucose metabolism: beyond weight gain. Cell. 2019;8(11):1336. PubMed PMC

Shamshoum H, Medak KD, Wright DC. Peripheral mechanisms of acute olanzapine induced metabolic dysfunction: a review of in vivo models and treatment approaches. Behav Brain Res. 2021;400:113049. doi:10.1016/j.bbr.2020.113049 PubMed DOI

Castela I, Morais J, Barreiros‐Mota I, et al. Decreased adiponectin/leptin ratio relates to insulin resistance in adults with obesity. Am J Physiol‐Endocrinol Metab. 2023;324(2):E115‐E119. doi:10.1152/ajpendo.00273.2022 PubMed DOI

Senkus KE, Crowe‐White KM, Bolland AC, Locher JL, Ard JD. Changes in adiponectin:leptin ratio among older adults with obesity following a 12‐month exercise and diet intervention. Nutr Diabetes. 2022;12(1):1‐7. doi:10.1038/s41387-022-00207-1 PubMed DOI PMC

Chen VC‐H, Chen C‐H, Chiu Y‐H, Lin TY, Li FC, Lu ML. Leptin/adiponectin ratio as a potential biomarker for metabolic syndrome in patients with schizophrenia. Psychoneuroendocrinology. 2018;92:34‐40. PubMed

Horska K, Kotolova H, Karpisek M, et al. Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long‐acting formulation. Toxicol Appl Pharmacol. 2020;406:115214. doi:10.1016/j.taap.2020.115214 PubMed DOI

Prida E, Álvarez‐Delgado S, Pérez‐Lois R, et al. Liver brain interactions: focus on FGF21 a systematic review. Int J Mol Sci. 2022;23(21):13318. doi:10.3390/ijms232113318 PubMed DOI PMC

Zhang Q, Deng C, Huang X‐F. The role of ghrelin signalling in second‐generation antipsychotic‐induced weight gain. Psychoneuroendocrinology. 2013;38(11):2423‐2438. PubMed

Weston‐Green K, Babic I, de Santis M, et al. Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration. J Biomed Sci. 2018;25(1):40. doi:10.1186/s12929-018-0437-1 PubMed DOI PMC

Chang S‐C, Goh KK, Lu M‐L. Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: state‐of‐the‐art and future perspectives. World J Psychiatry. 2021;11(10):696‐710. doi:10.5498/wjp.v11.i10.696 PubMed DOI PMC

Singh R, Bansal Y, Medhi B, Kuhad A. Antipsychotics‐induced metabolic alterations: recounting the mechanistic insights, therapeutic targets and pharmacological alternatives. Eur J Pharmacol. 2019;844:231‐240. doi:10.1016/j.ejphar.2018.12.003 PubMed DOI

Fernø J, Vik‐Mo AO, Jassim G, et al. Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver. Psychopharmacology (Berl). 2009;203(1):73‐84. doi:10.1007/s00213-008-1370-x PubMed DOI

Lilley E, Stanford SC, Kendall DE, et al. ARRIVE 2.0 and the British Journal of pharmacology: updated guidance for 2020. Br J Pharmacol. 2020;177(16):3611‐3616. doi:10.1111/bph.15178 PubMed DOI PMC

Ruda‐Kucerova J, Babinska Z, Amchova P, et al. Reactivity to addictive drugs in the methylazoxymethanol (MAM) model of schizophrenia in male and female rats. World J Biol Psychiatry. 2017;18(2):129‐142. PubMed

Ruda‐Kucerova J, Babinska Z, Stark T, Micale V. Suppression of methamphetamine self‐administration by ketamine pre‐treatment is absent in the methylazoxymethanol (MAM) rat model of schizophrenia. Neurotox Res. 2017;32(1):121‐133. PubMed

Drazanova E, Ruda‐Kucerova J, Kratka L, et al. Different effects of prenatal MAM vs. perinatal THC exposure on regional cerebral blood perfusion detected by arterial spin labelling MRI in rats. Sci Rep. 2019;9(1):6062. doi:10.1038/s41598-019-42532-z PubMed DOI PMC

Stark T, Ruda‐Kucerova J, Iannotti FA, et al. Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia. Neuropharmacology. 2019;146:212‐221. doi:10.1016/j.neuropharm.2018.11.035 PubMed DOI

Stark T, Di Bartolomeo M, Di Marco R, et al. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. Biochem Pharmacol. 2020;177:114004. doi:10.1016/j.bcp.2020.114004 PubMed DOI

Stark T, Iannotti FA, Di Martino S, et al. Early blockade of CB1 receptors ameliorates schizophrenia‐like alterations in the neurodevelopmental MAM model of schizophrenia. Biomolecules. 2022;12(1):108. PubMed PMC

Di Bartolomeo M, Stark T, Di Martino S, et al. The effects of Peripubertal THC exposure in neurodevelopmental rat models of psychopathology. Int J Mol Sci. 2023;24(4):3907. PubMed PMC

Kucera J, Horska K, Hruska P, et al. Interacting effects of the MAM model of schizophrenia and antipsychotic treatment: untargeted proteomics approach in adipose tissue. Prog Neuropsychopharmacol Biol Psychiatry. 2021;108:110165. doi:10.1016/j.pnpbp.2020.110165 PubMed DOI

Kapur S, VanderSpek SC, Brownlee BA, et al. Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther. 2003;305(2):625‐631. doi:10.1124/jpet.102.046987 PubMed DOI

Diehl K‐H, Hull R, Morton D, et al. A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol. 2001;21(1):15‐23. doi:10.1002/jat.727 PubMed DOI

Binó L, Veselá I, Papežíková I, et al. The depletion of p38alpha kinase upregulates NADPH oxidase 2/NOX2/gp91 expression and the production of superoxide in mouse embryonic stem cells. Arch Biochem Biophys. 2019;671:18‐26. doi:10.1016/j.abb.2019.06.001 PubMed DOI

Perry BI, McIntosh G, Weich S, Singh S, Rees K. The association between first‐episode psychosis and abnormal glycaemic control: systematic review and meta‐analysis. Lancet Psychiatry. 2016;3(11):1049‐1058. PubMed

Pillinger T, Beck K, Stubbs B, Howes OD. Cholesterol and triglyceride levels in first‐episode psychosis: systematic review and meta‐analysis. Br J Psychiatry. 2017;211(6):339‐349. PubMed PMC

Garrido‐Torres N, Rocha‐Gonzalez I, Alameda L, et al. Metabolic syndrome in antipsychotic‐naive patients with first‐episode psychosis: a systematic review and meta‐analysis. Psychol Med. 2021;51(14):2307‐2320. PubMed

Garrido‐Torres N, Ruiz‐Veguilla M, Alameda L, et al. Prevalence of metabolic syndrome and related factors in a large sample of antipsychotic naïve patients with first‐episode psychosis: baseline results from the PAFIP cohort. Schizophr Res. 2022;246:277‐285. PubMed

Kowalchuk C, Castellani LN, Chintoh A, Remington G, Giacca A, Hahn MK. Antipsychotics and glucose metabolism: how brain and body collide. Am J Physiol‐Endocrinol Metab. 2019;316(1):E1‐E15. doi:10.1152/ajpendo.00164.2018 PubMed DOI

Misiak B, Stańczykiewicz B, Łaczmański Ł, Frydecka D. Lipid profile disturbances in antipsychotic‐naive patients with first‐episode non‐affective psychosis: a systematic review and meta‐analysis. Schizophr Res. 2017;190:18‐27. PubMed

Hussain G, Anwar H, Rasul A, et al. Lipids as biomarkers of brain disorders. Crit Rev Food Sci Nutr. 2019;60:351‐374. PubMed

Steen VM, Skrede S, Polushina T, et al. Genetic evidence for a role of the SREBP transcription system and lipid biosynthesis in schizophrenia and antipsychotic treatment. Eur Neuropsychopharmacol. 2017;27(6):589‐598. PubMed

Skrede S, Steen VM, Fernø J. Antipsychotic‐induced increase in lipid biosynthesis: activation through inhibition? J Lipid Res. 2013;54(2):307‐309. PubMed PMC

Lee J, Costa‐Dookhan K, Panganiban K, et al. Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: a pilot study. Front Psych. 2023;14:1169787. doi:10.3389/fpsyt.2023.1169787 PubMed DOI PMC

Qing Y, Yang J, Wan C. Increased serum fibroblast growth factor 21 levels in patients with schizophrenia. Aust N Z J Psychiatry. 2015;49(9):849‐850. PubMed

Talaei A, Farkhondeh T, Forouzanfar F. Fibroblast growth factor: promising target for schizophrenia. Curr Drug Targets. 2020;21(13):1344‐1353. doi:10.2174/1389450121666200628114843 PubMed DOI

Khasanova AK, Dobrodeeva VS, Shnayder NA, et al. Blood and urinary biomarkers of antipsychotic‐induced metabolic syndrome. Metabolites. 2022;12(8):726. doi:10.3390/metabo12080726 PubMed DOI PMC

Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti‐obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21(3):201‐223. doi:10.1038/s41573-021-00337-8 PubMed DOI PMC

Shao W, Jin T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis Transl Med. 2022;8(1):19‐25. doi:10.1016/j.cdtm.2021.08.005 PubMed DOI PMC

Harrison SA, Ruane PJ, Freilich B, et al. A randomized, double‐blind, placebo‐controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis. JHEP Rep. 2023;5(1):100563. doi:10.1016/j.jhepr.2022.100563 PubMed DOI PMC

Fernø J, Ersland KM, Duus IH, et al. Olanzapine depot exposure in male rats: dose‐dependent lipogenic effects without concomitant weight gain. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2015;25(6):923‐932. doi:10.1016/j.euroneuro.2015.03.002 PubMed DOI

Russell JC, Proctor SD. Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis. Cardiovasc Pathol. 2006;15(6):318‐330. PubMed

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