Biological mechanisms underpinning the association between weight gain and antipsychotic treatment of psychosis patients and related rodent model

• Grant number: 22/15283-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: May 09, 2023
• End date: May 08, 2024
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Cristina Marta Del-Ben
• Grantee: Camila Marcelino Loureiro
• Supervisor: Gavin Paul Reynolds
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Sheffield Hallam University, England
• Associated to the scholarship: 20/15752-1 - Cannabis use, childhood trauma and endocannabinoids and glutamatergic variants: risk for psychosis, BP.PD

Abstract

Weight gain is a critical issue in patients with psychosis, mainly associated with antipsychotic treatment. Preclinical models showed that antipsychotic treatment induces weight gain providing evidence for the metabolic side effects of antipsychotics. However, if the rapid weight gain seen in most patients on newly initiated antipsychotics is determined by epigenetic factors is not clear, as there is no validated tool for predicting the risk of weight gain in psychosis. We aim to explore the epigenetic biomarkers of six candidate genes associated with weight gain (adrenoceptor alpha-2A receptor: ADRA2A, cannabinoid receptor 1: CNR1, serotonin 2C receptor: HTR2C, insulin-Induced gene 2: INSIG2, leptin: LEP, and melanocortin-4 Receptor: MC4R) in psychotic patients under pharmacological treatment. Using a rat olanzapine-induced weight gain model, we propose to quantify equivalent DNA methylation changes in brain and blood samples in the same six genes proposed above, as well as hypothalamic peptides. We will include information from DNA blood using a retrospective study with samples of first-episode psychosis (FEP) patients (n=60), and a prospective study which comprises patients in early stages of psychosis (n=50), both recruited from the Ribeirão Preto catchment area followed for twelve and six months, retrospectively. Sociodemographic, clinical and metabolic data will be reviewed from medical records and standard assessments. We will also include two groups of 12 female Lister hooded rats dosed with vehicle or olanzapine. The effect on body weight will be assessed following daily drug administration over 10 days. For humans and rodents, DNA methylation will be analysed by pyrosequencing. Statistical data will be analysed using logistic/linear regression models. In humans, changes in DNA methylation in selected genes may reveal a relationship between weight gain and antipsychotic treatment in psychosis. In rodents, our working hypothesis is to test if altered epigenetic and hypothalamic markers will be equivalent to the changes seen in humans. (AU)