MECHANISMS MEDIATING TREATMENT RESISTANCE IN QATARI PATIENTS WITH SCHIZOPHRENIA

Abstract

Schizophrenia is a severe mental health disorder affecting over 21 million people globally, with a significant burden on individuals and healthcare systems. Treatment-resistant schizophrenia (TRS) poses a challenge, with patients exhibiting resistance to standard antipsychotic treatments. This thesis aims to understand the molecular mechanisms underlying TRS in the Qatari population, focusing on inflammation-related pathways. A cross-sectional study was conducted on Qatari patients with schizophrenia, comparing TRS and non-treatment-resistant (NTRS) groups to controls. Routine laboratory blood parameters and inflammation-associated proteins were explored as potential diagnostic and predictive biomarkers for treatment resistance. Lymphocytes was significantly higher in TRS compared to controls. While platelet counts were higher in the NTRS group, a higher mean platelet volume was observed in both schizophrenia groups. Through Olink-based proteomics, this study identified three significant pathways when 21 TRS-specific proteins were compared with controls: AMPK signaling, cellular senescence, and longevity regulation, all featuring downregulation of SIRT1 and TSC1 proteins. In TRS, compared to the NTRS group, CPOX, NAGA, and EDNRB were upregulated. Correlation analysis revealed a significant negative relationship between CPOX expression and positive symptoms in schizophrenia, as well as a moderate positive correlation between EDNRB expression and plasma levels of clozapine and its metabolite norclozapine, suggesting potential links between these secreted proteins and symptom severity or treatment response. These findings suggest a link between treatment resistance in schizophrenia and inflammation-related pathways. Further research is needed to validate these results and explore the therapeutic potential of targeting these pathways in TRS. The study highlights the importance of understanding the biological underpinnings of TRS to develop more effective treatments and improve patient outcomes.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences