Developing a risk assessment model for treatment-resistant schizophrenia: The role of niacin receptor GPR109A and prostaglandin receptors DP₁, EP₂, and EP₄ in the niacin-induced flushing pathway

Schizophrenia patients show attenuated niacin flush responses compared to healthy controls (HC) attributed to abnormalities in the niacin-induced flushing pathway. Underlying immunological abnormalities may reduce the niacin receptor GPR109A's response and implicated in treatment-resistant schizophrenia (TRS). This pathway involves GPR109A and the downstream vasodilatory prostaglandins (PGs), PGD₂ and PGE₂, along with their receptors DP₁, EP₂, and EP₄, contributing to vasodilation and neuroprotection. We hypothesized that the niacin receptor GPR109A, PGs, and their receptors play a significant role in the pathogenesis of TRS. We aimed to investigate GPR109A, DP₁, PGD₂, PGE₂, EP₂, and EP₄ as potential biomarkers for identifying TRS and construct a risk assessment model for TRS. We recruited 58 TRS, 67 NTRS patients, and 115 HC. We observed significant differences in niacin flush responses and expression levels of GPR109A, PGE₂, DP₁, EP₂, and EP₄ between the schizophrenia and HC groups. TRS group exhibited lower expression levels of GPR109A, DP₁, EP₂, and EP₄ than NTRS group. Receiver operating characteristic curve analysis combining the six markers for schizophrenia versus HC yielded an area under the curve (AUC) of 0.98, whereas an analysis combining the four markers for TRS versus NTRS yielded an AUC of 0.91. Niacin-induced flushing signaling cascade enrichment is linked to the intensity of the inflammatory response, with associated mediators and their receptor affinities potentially regulating pharmacological effects. These findings suggest that the niacin receptor GPR109A and PG receptors DP₁, EP₂, and EP₄, which are involved in the niacin-induced flushing pathway, may serve as biomarkers for predicting TRS.