A Biological Investigation of the Role of Omega-3 Fatty Acids on Psychopathology in Clinical High Risk of Psychosis

Background: Psychosis is a multifactorial disorder and one among the top 15 causes of disability worldwide. Availability of complex, expensive and incomplete treatment modalities for psychosis increases the need of more investigations in understanding the pathophysiology and prevent development of the disease at an early stage. The current thesis focuses on the therapeutic role of omega-3 fatty acids (FAs) and investigates the biological mechanism underpinning the omega-3 related clinical outcome at clinical high risk (CHR) of psychosis. Methods: Initially, a systematic literature was performed to understand the existing evidence of omega-3 associated improvement in functional outcome in CHR participants. Then using baseline and follow-up plasma samples of the CHR subjects from the NEURAPRO clinical trial, the role of plasma immune markers and the plasma proteomic pathways on omega-3 associated improvement in clinical outcome was investigated. A total of 285 CHR participants aged 18.97 ± 4.49 years (mean ± SD) were included in this study. The molecular percentage of erythrocyte membrane FAs levels which are the markers of dietary omega-3 intake were quantified using the gas-chromatography. First the mediating role of plasma immune markers on omega-3 associated clinical outcomes was investigated. Secondly, using support vector machine learning techniques, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. Finally, using mass-spectrometry based proteomic analysis at baseline and 6-month follow-up plasma samples, we investigated the plasma proteomic pathways associated with omega-3 FAs and the mediating role of plasma proteins on omega-3 associated clinical improvement in psychosis. Results:The systematic provided a mixed results regarding the association of omega-3 FAs with functional outcome in CHR state. In the NEURAPRO clinical trial, plasma immune markers expressed an inverse association with omega-3 FAs both in cross-sectional and longitudinal analysis. Although plasma immune markers did not provide any mediating effect on omega-3 associated clinical outcome in CHR participants. In the prediction models, baseline parameters of both clinical and biological markers did not predictthe functional outcome and addition of biomarker data with clinical data did not improve prediction of 12-month functional outcome compared to the model based on the baseline clinical data alone. Finally, 6-month change in okmegha-3 FAs associated significantly with plasma proteins of complement and coagulation pathways. Furthermore, the complement and coagulation pathway proteins showed a significant mediating effect on omega-3 associated reduction in psychotic symptoms and improvement in functional outcome and cognition in CHR participants. Conclusion: Overall, the thesis has provided vital biological and clinical effects of omega-3 FAs in CHR state. The immune-assay results indicated a significant anti-inflammatory property of omega-3 FAs on plasma immune markers. Our proteomic analysis for the first time, has provided a relationship of complement and coagulation pathway proteins with functional outcome in CHR state. Furthermore, the mediation analysis indicated the involvement of complement and coagulation protein associated molecular mechanisms in omega-3 related clinical improvement in CHR state.