Molecular mechanisms of antidepressant refractoriness in adults, adolescents, and children with depression

• Grant number: 24/22955-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2025
• End date: September 30, 2028
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Daniel Martins-de-Souza
• Grantee: Caio Henrique de Souza Ferreira Berdeville
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 23/14968-9 - The quest for antidepressant treatment response biomarkers: identifying the potential candidates, AP.R

Abstract

The Major Depressive Disorder (MDD) is characterized by depressive mood and anhedonia, affecting almost 280 million people worldwide. In children and adolescents, irritability may substitute sadness as a cardinal symptom. Recently, both proteomics and metabolomics have been applied to the identification of potential biomarkers for adults with MDD. However, the use of omic approaches to the understanding of MDD in children and adolescents is still poorly understood. This scenario led to a gap related to the pathophysiology and candidate biomarkers, both for diagnosis and prediction of response to antidepressants. Therefore, the aim of this project is to identify molecular mechanisms associated with the refractoriness to fluoxetine in children and adolescents for the purpose of identifying potential biomarkers specific to these life stages. To achieve this goal, a prospective and observational cohort study will be conducted, recruiting adults, adolescents, and children (n = 90) and their controls (n = 90), collecting blood samples before and after use of fluoxetine. The plasma of the participants will be submitted to a proteomic and metabolomic evaluation based on mass spectroscopy associated with liquid chromatography. Data will be analyzed to assess differentially expressed proteins and metabolites, pathway enrichment, interaction between molecules, and the elaboration of a Receiver Operating Characteristic (ROC) curve. The up- and down- regulated pathways identified between groups will be validated in vitro with the treatment with the participants plasma in neurons derivered from induced pluripotent stem cell genereted from patients with TD. It is expected that this project led to the proposition of a biomarkers panel that may allow a better distinction between good and poor responses to fluoxetine, also providing insights into processes relevant to the pathophysiology of MDD and the mechanism of refractoriness to its treatment.